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Neural stem cells in Parkinson’s disease: a role for neurogenesis defects in onset and progression

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Abstract

Parkinson’s disease (PD) is the second most common neurodegenerative disorder, leading to a variety of motor and non-motor symptoms. Interestingly, non-motor symptoms often appear a decade or more before the first signs of motor symptoms. Some of these non-motor symptoms are remarkably similar to those observed in cases of impaired neurogenesis and several PD-related genes have been shown to play a role in embryonic or adult neurogenesis. Indeed, animal models deficient in Nurr1, Pitx3, SNCA and PINK1 display deregulated embryonic neurogenesis and LRRK2 and VPS35 have been implicated in neuronal development-related processes such as Wnt/β-catenin signaling and neurite outgrowth. Moreover, adult neurogenesis is affected in both PD patients and PD animal models and is regulated by dopamine and dopaminergic (DA) receptors, by chronic neuroinflammation, such as that observed in PD, and by differential expression of wild-type or mutant forms of PD-related genes. Indeed, an increasing number of in vivo studies demonstrate a role for SNCA and LRRK2 in adult neurogenesis and in the generation and maintenance of DA neurons. Finally, the roles of PD-related genes, SNCA, LRRK2, VPS35, Parkin, PINK1 and DJ-1 have been studied in NSCs, progenitor cells and induced pluripotent stem cells, demonstrating a role for some of these genes in stem/progenitor cell proliferation and maintenance. Together, these studies strongly suggest a link between deregulated neurogenesis and the onset and progression of PD and present strong evidence that, in addition to a neurodegenerative disorder, PD can also be regarded as a developmental disorder.

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Abbreviations

6-OHDA:

6-Hydroxydopamine

aPKC:

Atypical protein kinase C

DA:

Dopaminergic

DG:

Dentate gyrus

DKO:

Double knockout

dNB:

Drosophila neuroblasts

ESC:

Embryonic stem cell

iPSC:

Induced pluripotent stem cell

KD:

Knockdown

KO:

Knockout

LRRK2:

Leucine-rich repeat kinase 2

MPTP:

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine

NB:

Neuroblast

NF-κB:

Nuclear factor-kappaB

NPC:

Neural progenitor cell

NSC:

Neural stem cell

OB:

Olfactory bulb

PCNA:

Proliferating cell nuclear antigen

PD:

Parkinson’s disease

PINK1:

PTEN-induced putative kinase 1

RMS:

Rostral migratory stream

SN:

Substantia nigra

SNpc:

Substantia nigra pars compacta

SNCA:

α-Synuclein

SGZ:

Subgranular zone

SVZ:

Subventricular zone

TH:

Tyrosine hydroxylase

VPS35:

Vacuolar protein sorting 35

WT:

Wild type

References

  1. Parkinson J (2002) An essay on the shaking palsy. 1817. J Neuropsychiatry Clin Neurosci 14(2):223–236 (discussion 222)

    PubMed  Google Scholar 

  2. Dauer W, Przedborski S (2003) Parkinson’s disease: mechanisms and models. Neuron 39(6):889–909

    CAS  PubMed  Google Scholar 

  3. Jankovic J (2008) Parkinson’s disease: clinical features and diagnosis. J Neurol Neurosurg Psychiatry 79(4):368–376. doi:10.1136/jnnp.2007.131045

    CAS  PubMed  Google Scholar 

  4. Lemke MR, Brecht HM, Koester J, Kraus PH, Reichmann H (2005) Anhedonia, depression, and motor functioning in Parkinson’s disease during treatment with pramipexole. J Neuropsychiatry Clin Neurosci 17(2):214–220. doi:10.1176/appi.neuropsych.17.2.214

    CAS  PubMed  Google Scholar 

  5. Pluck GC, Brown RG (2002) Apathy in Parkinson’s disease. J Neurol Neurosurg Psychiatry 73(6):636–642

    CAS  PubMed Central  PubMed  Google Scholar 

  6. Isella V, Iurlaro S, Piolti R, Ferrarese C, Frattola L, Appollonio I, Melzi P, Grimaldi M (2003) Physical anhedonia in Parkinson’s disease. J Neurol Neurosurg Psychiatry 74(9):1308–1311

    CAS  PubMed Central  PubMed  Google Scholar 

  7. Fujiwara S, Kimura F, Hosokawa T, Ishida S, Sugino M, Hanafusa T (2011) Anhedonia in Japanese patients with Parkinson’s disease. Geriatr Gerontol Int 11(3):275–281. doi:10.1111/j.1447-0594.2010.00678.x

    PubMed  Google Scholar 

  8. Miura S, Kida H, Nakajima J, Noda K, Nagasato K, Ayabe M, Aizawa H, Hauser M, Taniwaki T (2012) Anhedonia in Japanese patients with Parkinson’s disease: analysis using the Snaith–Hamilton Pleasure Scale. Clin Neurol Neurosurg 114(4):352–355. doi:10.1016/j.clineuro.2011.11.008

    PubMed  Google Scholar 

  9. Slaughter JR, Slaughter KA, Nichols D, Holmes SE, Martens MP (2001) Prevalence, clinical manifestations, etiology, and treatment of depression in Parkinson’s disease. J Neuropsychiatry Clin Neurosci 13(2):187–196

    CAS  PubMed  Google Scholar 

  10. Menza MA, Robertson-Hoffman DE, Bonapace AS (1993) Parkinson’s disease and anxiety: comorbidity with depression. Biol Psychiatry 34(7):465–470

    CAS  PubMed  Google Scholar 

  11. Doty RL, Deems DA, Stellar S (1988) Olfactory dysfunction in parkinsonism: a general deficit unrelated to neurologic signs, disease stage, or disease duration. Neurology 38(8):1237–1244

    CAS  PubMed  Google Scholar 

  12. Mesholam RI, Moberg PJ, Mahr RN, Doty RL (1998) Olfaction in neurodegenerative disease: a meta-analysis of olfactory functioning in Alzheimer’s and Parkinson’s diseases. Arch Neurol 55(1):84–90

    CAS  PubMed  Google Scholar 

  13. Hawkes CH, Shephard BC, Daniel SE (1997) Olfactory dysfunction in Parkinson’s disease. J Neurol Neurosurg Psychiatry 62(5):436–446

    CAS  PubMed Central  PubMed  Google Scholar 

  14. Shulman LM, Taback RL, Bean J, Weiner WJ (2001) Comorbidity of the nonmotor symptoms of Parkinson’s disease. Mov Disord 16(3):507–510

    CAS  PubMed  Google Scholar 

  15. Tandberg E, Larsen JP, Karlsen K (1999) Excessive daytime sleepiness and sleep benefit in Parkinson’s disease: a community-based study. Mov Disord 14(6):922–927

    CAS  PubMed  Google Scholar 

  16. Buter TC, van den Hout A, Matthews FE, Larsen JP, Brayne C, Aarsland D (2008) Dementia and survival in Parkinson disease: a 12-year population study. Neurology 70(13):1017–1022. doi:10.1212/01.wnl.0000306632.43729.24

    CAS  PubMed  Google Scholar 

  17. Hely MA, Reid WG, Adena MA, Halliday GM, Morris JG (2008) The Sydney multicenter study of Parkinson’s disease: the inevitability of dementia at 20 years. Mov Disord 23(6):837–844. doi:10.1002/mds.21956

    PubMed  Google Scholar 

  18. Aarsland D, Andersen K, Larsen JP, Lolk A, Kragh-Sorensen P (2003) Prevalence and characteristics of dementia in Parkinson disease: an 8-year prospective study. Arch Neurol 60(3):387–392

    PubMed  Google Scholar 

  19. Savica R, Rocca WA, Ahlskog JE (2010) When does Parkinson disease start? Arch Neurol 67(7):798–801. doi:10.1001/archneurol.2010.135

    PubMed  Google Scholar 

  20. Jellinger KA (2012) Neuropathology of sporadic Parkinson’s disease: evaluation and changes of concepts. Mov Disord 27(1):8–30. doi:10.1002/mds.23795

    CAS  PubMed  Google Scholar 

  21. Dickson DW, Braak H, Duda JE, Duyckaerts C, Gasser T, Halliday GM, Hardy J, Leverenz JB, Del Tredici K, Wszolek ZK, Litvan I (2009) Neuropathological assessment of Parkinson’s disease: refining the diagnostic criteria. Lancet Neurol 8(12):1150–1157. doi:10.1016/s1474-4422(09)70238-8

    CAS  PubMed  Google Scholar 

  22. Riederer P, Wuketich S (1976) Time course of nigrostriatal degeneration in Parkinson’s disease. A detailed study of influential factors in human brain amine analysis. J Neural Transm 38(3–4):277–301

    CAS  PubMed  Google Scholar 

  23. Scherman D, Desnos C, Darchen F, Pollak P, Javoy-Agid F, Agid Y (1989) Striatal dopamine deficiency in Parkinson’s disease: role of aging. Ann Neurol 26(4):551–557. doi:10.1002/ana.410260409

    CAS  PubMed  Google Scholar 

  24. Nuytemans K, Theuns J, Cruts M, Van Broeckhoven C (2010) Genetic etiology of Parkinson disease associated with mutations in the SNCA, PARK2, PINK1, PARK7, and LRRK2 genes: a mutation update. Hum Mutat 31(7):763–780. doi:10.1002/humu.21277

    CAS  PubMed Central  PubMed  Google Scholar 

  25. Gasser T (2009) Molecular pathogenesis of Parkinson disease: insights from genetic studies. Expert Rev Mol Med 11:e22. doi:10.1017/s1462399409001148

    PubMed  Google Scholar 

  26. Sanchez-Danes A, Richaud-Patin Y, Carballo-Carbajal I, Jimenez-Delgado S, Caig C, Mora S, Di Guglielmo C, Ezquerra M, Patel B, Giralt A, Canals JM, Memo M, Alberch J, Lopez-Barneo J, Vila M, Cuervo AM, Tolosa E, Consiglio A, Raya A (2012) Disease-specific phenotypes in dopamine neurons from human iPS-based models of genetic and sporadic Parkinson’s disease. EMBO Mol Med 4(5):380–395. doi:10.1002/emmm.201200215

    CAS  PubMed Central  PubMed  Google Scholar 

  27. Lesage S, Brice A (2012) Role of Mendelian genes in “sporadic” Parkinson’s disease. Parkinsonism Relat Disord 18(Suppl 1):S66–70. doi:10.1016/s1353-8020(11)70022-0

    PubMed  Google Scholar 

  28. Tolosa E, Gaig C, Santamaria J, Compta Y (2009) Diagnosis and the premotor phase of Parkinson disease. Neurology 72(7 Suppl):S12–20. doi:10.1212/WNL.0b013e318198db11

    PubMed  Google Scholar 

  29. Shiba M, Bower JH, Maraganore DM, McDonnell SK, Peterson BJ, Ahlskog JE, Schaid DJ, Rocca WA (2000) Anxiety disorders and depressive disorders preceding Parkinson’s disease: a case–control study. Mov Disord 15(4):669–677

    CAS  PubMed  Google Scholar 

  30. O’Sullivan SS, Williams DR, Gallagher DA, Massey LA, Silveira-Moriyama L, Lees AJ (2008) Nonmotor symptoms as presenting complaints in Parkinson’s disease: a clinicopathological study. Mov Disord 23(1):101–106. doi:10.1002/mds.21813

    PubMed  Google Scholar 

  31. Revest JM, Dupret D, Koehl M, Funk-Reiter C, Grosjean N, Piazza PV, Abrous DN (2009) Adult hippocampal neurogenesis is involved in anxiety-related behaviors. Mol Psychiatry 14(10):959–967. doi:10.1038/mp.2009.15

    PubMed  Google Scholar 

  32. Malberg JE, Eisch AJ, Nestler EJ, Duman RS (2000) Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. J Neurosci 20(24):9104–9110

    CAS  PubMed  Google Scholar 

  33. Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S, Weisstaub N, Lee J, Duman R, Arancio O, Belzung C, Hen R (2003) Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science 301(5634):805–809. doi:10.1126/science.1083328

    CAS  PubMed  Google Scholar 

  34. Perera TD, Coplan JD, Lisanby SH, Lipira CM, Arif M, Carpio C, Spitzer G, Santarelli L, Scharf B, Hen R, Rosoklija G, Sackeim HA, Dwork AJ (2007) Antidepressant-induced neurogenesis in the hippocampus of adult nonhuman primates. J Neurosci 27(18):4894–4901. doi:10.1523/jneurosci.0237-07.2007

    CAS  PubMed  Google Scholar 

  35. Schoenfeld TJ, Cameron HA (2014) Adult Neurogenesis and mental illness. Neuropsychopharmacology. doi:10.1038/npp.2014.230

  36. Morrison SJ (2001) Neuronal potential and lineage determination by neural stem cells. Curr Opin Cell Biol 13(6):666–672

    CAS  PubMed  Google Scholar 

  37. Hartfuss E, Galli R, Heins N, Gotz M (2001) Characterization of CNS precursor subtypes and radial glia. Dev Biol 229(1):15–30. doi:10.1006/dbio.2000.9962

    CAS  PubMed  Google Scholar 

  38. Noctor SC, Flint AC, Weissman TA, Wong WS, Clinton BK, Kriegstein AR (2002) Dividing precursor cells of the embryonic cortical ventricular zone have morphological and molecular characteristics of radial glia. J Neurosci 22(8):3161–3173 (20026299)

    CAS  PubMed  Google Scholar 

  39. Malatesta P, Hartfuss E, Gotz M (2000) Isolation of radial glial cells by fluorescent-activated cell sorting reveals a neuronal lineage. Development 127(24):5253–5263

    CAS  PubMed  Google Scholar 

  40. Tarabykin V, Stoykova A, Usman N, Gruss P (2001) Cortical upper layer neurons derive from the subventricular zone as indicated by Svet1 gene expression. Development 128(11):1983–1993

    CAS  PubMed  Google Scholar 

  41. Englund C, Fink A, Lau C, Pham D, Daza RA, Bulfone A, Kowalczyk T, Hevner RF (2005) Pax6, Tbr2, and Tbr1 are expressed sequentially by radial glia, intermediate progenitor cells, and postmitotic neurons in developing neocortex. J Neurosci 25(1):247–251. doi:10.1523/jneurosci.2899-04.2005

    CAS  PubMed  Google Scholar 

  42. Nieto M, Monuki ES, Tang H, Imitola J, Haubst N, Khoury SJ, Cunningham J, Gotz M, Walsh CA (2004) Expression of Cux-1 and Cux-2 in the subventricular zone and upper layers II-IV of the cerebral cortex. J Comp Neurol 479(2):168–180. doi:10.1002/cne.20322

    CAS  PubMed  Google Scholar 

  43. Zimmer C, Tiveron MC, Bodmer R, Cremer H (2004) Dynamics of Cux2 expression suggests that an early pool of SVZ precursors is fated to become upper cortical layer neurons. Cereb Cortex 14(12):1408–1420. doi:10.1093/cercor/bhh102

    PubMed  Google Scholar 

  44. Altman J, Das GD (1965) Autoradiographic and histological evidence of postnatal hippocampal neurogenesis in rats. J Comp Neurol 124(3):319–335

    CAS  PubMed  Google Scholar 

  45. Curtis MA, Kam M, Nannmark U, Anderson MF, Axell MZ, Wikkelso C, Holtas S, van Roon-Mom WM, Bjork-Eriksson T, Nordborg C, Frisen J, Dragunow M, Faull RL, Eriksson PS (2007) Human neuroblasts migrate to the olfactory bulb via a lateral ventricular extension. Science 315(5816):1243–1249. doi:10.1126/science.1136281

    CAS  PubMed  Google Scholar 

  46. Eriksson PS, Perfilieva E, Bjork-Eriksson T, Alborn AM, Nordborg C, Peterson DA, Gage FH (1998) Neurogenesis in the adult human hippocampus. Nat Med 4(11):1313–1317. doi:10.1038/3305

    CAS  PubMed  Google Scholar 

  47. Sanai N, Tramontin AD, Quinones-Hinojosa A, Barbaro NM, Gupta N, Kunwar S, Lawton MT, McDermott MW, Parsa AT, Manuel-Garcia Verdugo J, Berger MS, Alvarez-Buylla A (2004) Unique astrocyte ribbon in adult human brain contains neural stem cells but lacks chain migration. Nature 427(6976):740–744. doi:10.1038/nature02301

    CAS  PubMed  Google Scholar 

  48. Kam M, Curtis MA, McGlashan SR, Connor B, Nannmark U, Faull RL (2009) The cellular composition and morphological organization of the rostral migratory stream in the adult human brain. J Chem Neuroanat 37(3):196–205. doi:10.1016/j.jchemneu.2008.12.009

    CAS  PubMed  Google Scholar 

  49. Winner B, Cooper-Kuhn CM, Aigner R, Winkler J, Kuhn HG (2002) Long-term survival and cell death of newly generated neurons in the adult rat olfactory bulb. Eur J Neurosci 16(9):1681–1689

    PubMed  Google Scholar 

  50. Kempermann G, Wiskott L, Gage FH (2004) Functional significance of adult neurogenesis. Curr Opin Neurobiol 14(2):186–191. doi:10.1016/j.conb.2004.03.001

    CAS  PubMed  Google Scholar 

  51. Ernst A, Alkass K, Bernard S, Salehpour M, Perl S, Tisdale J, Possnert G, Druid H, Frisen J (2014) Neurogenesis in the striatum of the adult human brain. Cell 156(5):1072–1083. doi:10.1016/j.cell.2014.01.044

    CAS  PubMed  Google Scholar 

  52. Le W, Conneely OM, He Y, Jankovic J, Appel SH (1999) Reduced Nurr1 expression increases the vulnerability of mesencephalic dopamine neurons to MPTP-induced injury. J Neurochem 73(5):2218–2221

    CAS  PubMed  Google Scholar 

  53. Backman C, Perlmann T, Wallen A, Hoffer BJ, Morales M (1999) A selective group of dopaminergic neurons express Nurr1 in the adult mouse brain. Brain Res 851(1–2):125–132

    CAS  PubMed  Google Scholar 

  54. Zetterstrom RH, Williams R, Perlmann T, Olson L (1996) Cellular expression of the immediate early transcription factors Nurr1 and NGFI-B suggests a gene regulatory role in several brain regions including the nigrostriatal dopamine system. Brain Res Mol Brain Res 41(1–2):111–120

    CAS  PubMed  Google Scholar 

  55. Sacchetti P, Mitchell TR, Granneman JG, Bannon MJ (2001) Nurr1 enhances transcription of the human dopamine transporter gene through a novel mechanism. J Neurochem 76(5):1565–1572

    CAS  PubMed  Google Scholar 

  56. Liu H, Tao Q, Deng H, Ming M, Ding Y, Xu P, Chen S, Song Z, Le W (2013) Genetic analysis of NR4A2 gene in a large population of Han Chinese patients with Parkinson’s disease. Eur J Neurol 20(3):584–587. doi:10.1111/j.1468-1331.2012.03824.x

    CAS  PubMed  Google Scholar 

  57. Chu Y, Le W, Kompoliti K, Jankovic J, Mufson EJ, Kordower JH (2006) Nurr1 in Parkinson’s disease and related disorders. J Comp Neurol 494(3):495–514. doi:10.1002/cne.20828

    CAS  PubMed Central  PubMed  Google Scholar 

  58. Grimes DA, Han F, Panisset M, Racacho L, Xiao F, Zou R, Westaff K, Bulman DE (2006) Translated mutation in the Nurr1 gene as a cause for Parkinson’s disease. Mov Disord 21(7):906–909. doi:10.1002/mds.20820

    PubMed  Google Scholar 

  59. Le WD, Xu P, Jankovic J, Jiang H, Appel SH, Smith RG, Vassilatis DK (2003) Mutations in NR4A2 associated with familial Parkinson disease. Nat Genet 33(1):85–89. doi:10.1038/ng1066

    CAS  PubMed  Google Scholar 

  60. Xu PY, Liang R, Jankovic J, Hunter C, Zeng YX, Ashizawa T, Lai D, Le WD (2002) Association of homozygous 7048G7049 variant in the intron six of Nurr1 gene with Parkinson’s disease. Neurology 58(6):881–884

    CAS  PubMed  Google Scholar 

  61. Moran LB, Croisier E, Duke DC, Kalaitzakis ME, Roncaroli F, Deprez M, Dexter DT, Pearce RK, Graeber MB (2007) Analysis of alpha-synuclein, dopamine and parkin pathways in neuropathologically confirmed parkinsonian nigra. Acta Neuropathol 113(3):253–263. doi:10.1007/s00401-006-0181-6

    CAS  PubMed  Google Scholar 

  62. Jiang C, Wan X, He Y, Pan T, Jankovic J, Le W (2005) Age-dependent dopaminergic dysfunction in Nurr1 knockout mice. Exp Neurol 191(1):154–162. doi:10.1016/j.expneurol.2004.08.035

    CAS  PubMed  Google Scholar 

  63. Zhang L, Le W, Xie W (1001) Dani JA (2012) Age-related changes in dopamine signaling in Nurr1 deficient mice as a model of Parkinson’s disease. Neurobiol Aging 33(5):e1007–1016. doi:10.1016/j.neurobiolaging.2011.03.022

    Google Scholar 

  64. Imam SZ, Jankovic J, Ali SF, Skinner JT, Xie W, Conneely OM, Le WD (2005) Nitric oxide mediates increased susceptibility to dopaminergic damage in Nurr1 heterozygous mice. FASEB J 19(11):1441–1450. doi:10.1096/fj.04-3362com

    CAS  PubMed  Google Scholar 

  65. Le W, Conneely OM, Zou L, He Y, Saucedo-Cardenas O, Jankovic J, Mosier DR, Appel SH (1999) Selective agenesis of mesencephalic dopaminergic neurons in Nurr1-deficient mice. Exp Neurol 159(2):451–458. doi:10.1006/exnr.1999.7191

    CAS  PubMed  Google Scholar 

  66. Saijo K, Winner B, Carson CT, Collier JG, Boyer L, Rosenfeld MG, Gage FH, Glass CK (2009) A Nurr1/CoREST pathway in microglia and astrocytes protects dopaminergic neurons from inflammation-induced death. Cell 137(1):47–59. doi:10.1016/j.cell.2009.01.038

    CAS  PubMed Central  PubMed  Google Scholar 

  67. Yang YX, Latchman DS (2008) Nurr1 transcriptionally regulates the expression of alpha-synuclein. NeuroReport 19(8):867–871. doi:10.1097/WNR.0b013e3282ffda48

    CAS  PubMed  Google Scholar 

  68. Jacobs FM, van Erp S, van der Linden AJ, von Oerthel L, Burbach JP, Smidt MP (2009) Pitx3 potentiates Nurr1 in dopamine neuron terminal differentiation through release of SMRT-mediated repression. Development 136(4):531–540. doi:10.1242/dev.029769

    CAS  PubMed  Google Scholar 

  69. Smidt MP, Smits SM, Bouwmeester H, Hamers FP, van der Linden AJ, Hellemons AJ, Graw J, Burbach JP (2004) Early developmental failure of substantia nigra dopamine neurons in mice lacking the homeodomain gene Pitx3. Development 131(5):1145–1155. doi:10.1242/dev.01022

    CAS  PubMed  Google Scholar 

  70. O’Keeffe FE, Scott SA, Tyers P, O’Keeffe GW, Dalley JW, Zufferey R, Caldwell MA (2008) Induction of A9 dopaminergic neurons from neural stem cells improves motor function in an animal model of Parkinson’s disease. Brain 131(Pt 3):630–641. doi:10.1093/brain/awm340

    PubMed  Google Scholar 

  71. Garcia-Reitboeck P, Anichtchik O, Dalley JW, Ninkina N, Tofaris GK, Buchman VL, Spillantini MG (2013) Endogenous alpha-synuclein influences the number of dopaminergic neurons in mouse substantia nigra. Exp Neurol 248:541–545. doi:10.1016/j.expneurol.2013.07.015

    CAS  PubMed Central  PubMed  Google Scholar 

  72. d’Amora M, Angelini C, Marcoli M, Cervetto C, Kitada T, Vallarino M (2011) Expression of PINK1 in the brain, eye and ear of mouse during embryonic development. J Chem Neuroanat 41(2):73–85. doi:10.1016/j.jchemneu.2010.11.004

    PubMed  Google Scholar 

  73. Rice D, Barone S Jr (2000) Critical periods of vulnerability for the developing nervous system: evidence from humans and animal models. Environ Health Perspect 108(Suppl 3):511–533

    PubMed Central  PubMed  Google Scholar 

  74. Berthier A, Jimenez-Sainz J, Pulido R (2013) PINK1 regulates histone H3 trimethylation and gene expression by interaction with the polycomb protein EED/WAIT1. Proc Natl Acad Sci USA 110(36):14729–14734. doi:10.1073/pnas.1216844110

    CAS  PubMed Central  PubMed  Google Scholar 

  75. Anichtchik O, Diekmann H, Fleming A, Roach A, Goldsmith P, Rubinsztein DC (2008) Loss of PINK1 function affects development and results in neurodegeneration in zebrafish. J Neurosci 28(33):8199–8207. doi:10.1523/jneurosci.0979-08.2008

    CAS  PubMed  Google Scholar 

  76. Zechel S, Meinhardt A, Unsicker K, von Bohlen Und Halbach O (2010) Expression of leucine-rich-repeat-kinase 2 (LRRK2) during embryonic development. Int J Dev Neurosci 28(5):391–399. doi:10.1016/j.ijdevneu.2010.04.002

    CAS  PubMed  Google Scholar 

  77. Jaleel M, Nichols RJ, Deak M, Campbell DG, Gillardon F, Knebel A, Alessi DR (2007) LRRK2 phosphorylates moesin at threonine-558: characterization of how Parkinson’s disease mutants affect kinase activity. Biochem J 405(2):307–317. doi:10.1042/bj20070209

    CAS  PubMed Central  PubMed  Google Scholar 

  78. MacLeod D, Dowman J, Hammond R, Leete T, Inoue K, Abeliovich A (2006) The familial Parkinsonism gene LRRK2 regulates neurite process morphology. Neuron 52(4):587–593. doi:10.1016/j.neuron.2006.10.008

    CAS  PubMed  Google Scholar 

  79. Plowey ED, Cherra SJ 3rd, Liu YJ, Chu CT (2008) Role of autophagy in G2019S-LRRK2-associated neurite shortening in differentiated SH-SY5Y cells. J Neurochem 105(3):1048–1056. doi:10.1111/j.1471-4159.2008.05217.x

    CAS  PubMed Central  PubMed  Google Scholar 

  80. Parisiadou L, Xie C, Cho HJ, Lin X, Gu XL, Long CX, Lobbestael E, Baekelandt V, Taymans JM, Sun L, Cai H (2009) Phosphorylation of ezrin/radixin/moesin proteins by LRRK2 promotes the rearrangement of actin cytoskeleton in neuronal morphogenesis. J Neurosci 29(44):13971–13980. doi:10.1523/jneurosci.3799-09.2009

    CAS  PubMed Central  PubMed  Google Scholar 

  81. Dachsel JC, Behrouz B, Yue M, Beevers JE, Melrose HL, Farrer MJ (2010) A comparative study of Lrrk2 function in primary neuronal cultures. Parkinsonism Relat Disord 16(10):650–655. doi:10.1016/j.parkreldis.2010.08.018

    PubMed Central  PubMed  Google Scholar 

  82. Heo HY, Kim KS, Seol W (2010) Coordinate regulation of neurite outgrowth by LRRK2 and its interactor, Rab5. Exp Neurobiol 19(2):97–105. doi:10.5607/en.2010.19.2.97

    PubMed Central  PubMed  Google Scholar 

  83. Lin CH, Tsai PI, Wu RM, Chien CT (2010) LRRK2 G2019S mutation induces dendrite degeneration through mislocalization and phosphorylation of tau by recruiting autoactivated GSK3ss. J Neurosci 30(39):13138–13149. doi:10.1523/jneurosci.1737-10.2010

    CAS  PubMed  Google Scholar 

  84. Chan D, Citro A, Cordy JM, Shen GC, Wolozin B (2011) Rac1 protein rescues neurite retraction caused by G2019S leucine-rich repeat kinase 2 (LRRK2). J Biol Chem 286(18):16140–16149. doi:10.1074/jbc.M111.234005

    CAS  PubMed Central  PubMed  Google Scholar 

  85. Ramonet D, Daher JP, Lin BM, Stafa K, Kim J, Banerjee R, Westerlund M, Pletnikova O, Glauser L, Yang L, Liu Y, Swing DA, Beal MF, Troncoso JC, McCaffery JM, Jenkins NA, Copeland NG, Galter D, Thomas B, Lee MK, Dawson TM, Dawson VL, Moore DJ (2011) Dopaminergic neuronal loss, reduced neurite complexity and autophagic abnormalities in transgenic mice expressing G2019S mutant LRRK2. PLoS ONE 6(4):e18568. doi:10.1371/journal.pone.0018568

    CAS  PubMed Central  PubMed  Google Scholar 

  86. Winner B, Melrose HL, Zhao C, Hinkle KM, Yue M, Kent C, Braithwaite AT, Ogholikhan S, Aigner R, Winkler J, Farrer MJ, Gage FH (2011) Adult neurogenesis and neurite outgrowth are impaired in LRRK2 G2019S mice. Neurobiol Dis 41(3):706–716. doi:10.1016/j.nbd.2010.12.008

    CAS  PubMed Central  PubMed  Google Scholar 

  87. Maekawa T, Mori S, Sasaki Y, Miyajima T, Azuma S, Ohta E, Obata F (2012) The I2020T Leucine-rich repeat kinase 2 transgenic mouse exhibits impaired locomotive ability accompanied by dopaminergic neuron abnormalities. Mol Neurodegener 7:15. doi:10.1186/1750-1326-7-15

    CAS  PubMed Central  PubMed  Google Scholar 

  88. Sheng Z, Zhang S, Bustos D, Kleinheinz T, Le Pichon CE, Dominguez SL, Solanoy HO, Drummond J, Zhang X, Ding X, Cai F, Song Q, Li X, Yue Z, van der Brug MP, Burdick DJ, Gunzner-Toste J, Chen H, Liu X, Estrada AA, Sweeney ZK, Scearce-Levie K, Moffat JG, Kirkpatrick DS, Zhu H (2012) Ser1292 autophosphorylation is an indicator of LRRK2 kinase activity and contributes to the cellular effects of PD mutations. Sci Transl Med 4(164):164ra161. doi:10.1126/scitranslmed.3004485

    PubMed  Google Scholar 

  89. Stafa K, Trancikova A, Webber PJ, Glauser L, West AB, Moore DJ (2012) GTPase activity and neuronal toxicity of Parkinson’s disease-associated LRRK2 is regulated by ArfGAP1. PLoS Genet 8(2):e1002526. doi:10.1371/journal.pgen.1002526

    CAS  PubMed Central  PubMed  Google Scholar 

  90. Biosa A, Trancikova A, Civiero L, Glauser L, Bubacco L, Greggio E, Moore DJ (2013) GTPase activity regulates kinase activity and cellular phenotypes of Parkinson’s disease-associated LRRK2. Hum Mol Genet 22(6):1140–1156. doi:10.1093/hmg/dds522

    CAS  PubMed  Google Scholar 

  91. Cherra SJ 3rd, Steer E, Gusdon AM, Kiselyov K, Chu CT (2013) Mutant LRRK2 elicits calcium imbalance and depletion of dendritic mitochondria in neurons. Am J Pathol 182(2):474–484. doi:10.1016/j.ajpath.2012.10.027

    CAS  PubMed Central  PubMed  Google Scholar 

  92. Cho HJ, Liu G, Jin SM, Parisiadou L, Xie C, Yu J, Sun L, Ma B, Ding J, Vancraenenbroeck R, Lobbestael E, Baekelandt V, Taymans JM, He P, Troncoso JC, Shen Y, Cai H (2013) MicroRNA-205 regulates the expression of Parkinson’s disease-related leucine-rich repeat kinase 2 protein. Hum Mol Genet 22(3):608–620. doi:10.1093/hmg/dds470

    CAS  PubMed Central  PubMed  Google Scholar 

  93. Law BM, Spain VA, Leinster VH, Chia R, Beilina A, Cho HJ, Taymans JM, Urban MK, Sancho RM, Ramirez MB, Biskup S, Baekelandt V, Cai H, Cookson MR, Berwick DC, Harvey K (2014) A direct interaction between leucine-rich repeat kinase 2 and specific beta-tubulin isoforms regulates tubulin acetylation. J Biol Chem 289(2):895–908. doi:10.1074/jbc.M113.507913

    CAS  PubMed Central  PubMed  Google Scholar 

  94. Paus M, Kohl Z, Ben Abdallah NM, Galter D, Gillardon F, Winkler J (2013) Enhanced dendritogenesis and axogenesis in hippocampal neuroblasts of LRRK2 knockout mice. Brain Res 1497:85–100. doi:10.1016/j.brainres.2012.12.024

    CAS  PubMed  Google Scholar 

  95. Sancho RM, Law BM, Harvey K (2009) Mutations in the LRRK2 Roc-COR tandem domain link Parkinson’s disease to Wnt signalling pathways. Hum Mol Genet 18(20):3955–3968. doi:10.1093/hmg/ddp337

    CAS  PubMed Central  PubMed  Google Scholar 

  96. Berwick DC, Harvey K (2012) LRRK2 functions as a Wnt signaling scaffold, bridging cytosolic proteins and membrane-localized LRP6. Hum Mol Genet 21(22):4966–4979. doi:10.1093/hmg/dds342

    CAS  PubMed Central  PubMed  Google Scholar 

  97. Wang CL, Tang FL, Peng Y, Shen CY, Mei L, Xiong WC (2012) VPS35 regulates developing mouse hippocampal neuronal morphogenesis by promoting retrograde trafficking of BACE1. Biol Open 1(12):1248–1257. doi:10.1242/bio.20122451

    CAS  PubMed Central  PubMed  Google Scholar 

  98. Seroogy KB, Lundgren KH, Tran TM, Guthrie KM, Isackson PJ, Gall CM (1994) Dopaminergic neurons in rat ventral midbrain express brain-derived neurotrophic factor and neurotrophin-3 mRNAs. J Comp Neurol 342(3):321–334

  99. Gash DM, Zhang Z, Ovadia A, Cass WA, Yi A, Simmerman L, Russell D, Martin D, Lapchak PA, Collins F, Hoffer BJ, Gerhardt GA (1996) Functional recovery in parkinsonian monkeys treated with GDNF. Nature 380(6571):252–255. doi:10.1038/380252a0

    CAS  PubMed  Google Scholar 

  100. Skaper SD, Negro A, Facci L, Dal Toso R (1993) Brain-derived neurotrophic factor selectively rescues mesencephalic dopaminergic neurons from 2,4,5-trihydroxyphenylalanine-induced injury. J Neurosci Res 34(4):478–487. doi:10.1002/jnr.490340413

    CAS  PubMed  Google Scholar 

  101. Curtis MA, Eriksson PS, Faull RL (2007) Progenitor cells and adult neurogenesis in neurodegenerative diseases and injuries of the basal ganglia. Clin Exp Pharmacol Physiol 34(5–6):528–532. doi:10.1111/j.1440-1681.2007.04609.x

    CAS  PubMed  Google Scholar 

  102. Höglinger GU, Rizk P, Muriel MP, Duyckaerts C, Oertel WH, Caille I, Hirsch EC (2004) Dopamine depletion impairs precursor cell proliferation in Parkinson disease. Nat Neurosci 7(7):726–735. doi:10.1038/nn1265

    PubMed  Google Scholar 

  103. O’Sullivan SS, Johnson M, Williams DR, Revesz T, Holton JL, Lees AJ, Perry EK (2011) The effect of drug treatment on neurogenesis in Parkinson’s disease. Mov Disord 26(1):45–50. doi:10.1002/mds.23340

    PubMed  Google Scholar 

  104. Iwakura Y, Piao YS, Mizuno M, Takei N, Kakita A, Takahashi H, Nawa H (2005) Influences of dopaminergic lesion on epidermal growth factor-ErbB signals in Parkinson’s disease and its model: neurotrophic implication in nigrostriatal neurons. J Neurochem 93(4):974–983. doi:10.1111/j.1471-4159.2005.03073.x

    CAS  PubMed  Google Scholar 

  105. O’Keeffe GC, Tyers P, Aarsland D, Dalley JW, Barker RA, Caldwell MA (2009) Dopamine-induced proliferation of adult neural precursor cells in the mammalian subventricular zone is mediated through EGF. Proc Natl Acad Sci USA 106(21):8754–8759. doi:10.1073/pnas.0803955106

    PubMed Central  PubMed  Google Scholar 

  106. van den Berge SA, van Strien ME, Korecka JA, Dijkstra AA, Sluijs JA, Kooijman L, Eggers R, De Filippis L, Vescovi AL, Verhaagen J, van de Berg WD, Hol EM (2011) The proliferative capacity of the subventricular zone is maintained in the parkinsonian brain. Brain 134(Pt 11):3249–3263. doi:10.1093/brain/awr256

    PubMed  Google Scholar 

  107. van den Berge SA, Middeldorp J, Zhang CE, Curtis MA, Leonard BW, Mastroeni D, Voorn P, van de Berg WD, Huitinga I, Hol EM (2010) Longterm quiescent cells in the aged human subventricular neurogenic system specifically express GFAP-delta. Aging Cell 9(3):313–326. doi:10.1111/j.1474-9726.2010.00556.x

    PubMed  Google Scholar 

  108. Leonard BW, Mastroeni D, Grover A, Liu Q, Yang K, Gao M, Wu J, Pootrakul D, van den Berge SA, Hol EM, Rogers J (2009) Subventricular zone neural progenitors from rapid brain autopsies of elderly subjects with and without neurodegenerative disease. J Comp Neurol 515(3):269–294. doi:10.1002/cne.22040

    PubMed Central  PubMed  Google Scholar 

  109. Walton NM, Sutter BM, Chen HX, Chang LJ, Roper SN, Scheffler B, Steindler DA (2006) Derivation and large-scale expansion of multipotent astroglial neural progenitors from adult human brain. Development 133(18):3671–3681. doi:10.1242/dev.02541

    CAS  PubMed  Google Scholar 

  110. Wang S, Okun MS, Suslov O, Zheng T, McFarland NR, Vedam-Mai V, Foote KD, Roper SN, Yachnis AT, Siebzehnrubl FA, Steindler DA (2012) Neurogenic potential of progenitor cells isolated from postmortem human Parkinsonian brains. Brain Res 1464:61–72. doi:10.1016/j.brainres.2012.04.039

    CAS  PubMed Central  PubMed  Google Scholar 

  111. Kuzumaki N, Ikegami D, Imai S, Narita M, Tamura R, Yajima M, Suzuki A, Miyashita K, Niikura K, Takeshima H, Ando T, Ushijima T, Suzuki T (2010) Enhanced IL-1beta production in response to the activation of hippocampal glial cells impairs neurogenesis in aged mice. Synapse 64(9):721–728. doi:10.1002/syn.20800

    CAS  PubMed  Google Scholar 

  112. Kuzumaki N, Ikegami D, Tamura R, Sasaki T, Niikura K, Narita M, Miyashita K, Imai S, Takeshima H, Ando T, Igarashi K, Kanno J, Ushijima T, Suzuki T (2010) Hippocampal epigenetic modification at the doublecortin gene is involved in the impairment of neurogenesis with aging. Synapse 64(8):611–616. doi:10.1002/syn.20768

    CAS  PubMed  Google Scholar 

  113. Molofsky AV, Slutsky SG, Joseph NM, He S, Pardal R, Krishnamurthy J, Sharpless NE, Morrison SJ (2006) Increasing p16INK4a expression decreases forebrain progenitors and neurogenesis during ageing. Nature 443(7110):448–452. doi:10.1038/nature05091

    CAS  PubMed Central  PubMed  Google Scholar 

  114. He XJ, Nakayama H, Dong M, Yamauchi H, Ueno M, Uetsuka K, Doi K (2006) Evidence of apoptosis in the subventricular zone and rostral migratory stream in the MPTP mouse model of Parkinson disease. J Neuropathol Exp Neurol 65(9):873–882. doi:10.1097/01.jnen.0000235115.29440.ce

    CAS  PubMed  Google Scholar 

  115. He XJ, Yamauchi H, Uetsuka K, Nakayama H (2008) Neurotoxicity of MPTP to migrating neuroblasts: studies in acute and subacute mouse models of Parkinson’s disease. Neurotoxicology 29(3):413–420. doi:10.1016/j.neuro.2008.02.007

    CAS  PubMed  Google Scholar 

  116. Peng J, Xie L, Jin K, Greenberg DA, Andersen JK (2008) Fibroblast growth factor 2 enhances striatal and nigral neurogenesis in the acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson’s disease. Neuroscience 153(3):664–670. doi:10.1016/j.neuroscience.2008.02.063

    CAS  PubMed Central  PubMed  Google Scholar 

  117. Peng J, Andersen JK (2011) Mutant alpha-synuclein and aging reduce neurogenesis in the acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson’s disease. Aging Cell 10(2):255–262. doi:10.1111/j.1474-9726.2010.00656.x

    CAS  PubMed Central  PubMed  Google Scholar 

  118. Zhao M, Momma S, Delfani K, Carlen M, Cassidy RM, Johansson CB, Brismar H, Shupliakov O, Frisen J, Janson AM (2003) Evidence for neurogenesis in the adult mammalian substantia nigra. Proc Natl Acad Sci USA 100(13):7925–7930. doi:10.1073/pnas.1131955100

    CAS  PubMed Central  PubMed  Google Scholar 

  119. Shan X, Chi L, Bishop M, Luo C, Lien L, Zhang Z, Liu R (2006) Enhanced de novo neurogenesis and dopaminergic neurogenesis in the substantia nigra of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinson’s disease-like mice. Stem Cells 24(5):1280–1287. doi:10.1634/stemcells.2005-0487

    CAS  PubMed Central  PubMed  Google Scholar 

  120. Freundlieb N, Francois C, Tande D, Oertel WH, Hirsch EC, Hoglinger GU (2006) Dopaminergic substantia nigra neurons project topographically organized to the subventricular zone and stimulate precursor cell proliferation in aged primates. J Neurosci 26(8):2321–2325. doi:10.1523/jneurosci.4859-05.2006

    CAS  PubMed  Google Scholar 

  121. Tande D, Hoglinger G, Debeir T, Freundlieb N, Hirsch EC, Francois C (2006) New striatal dopamine neurons in MPTP-treated macaques result from a phenotypic shift and not neurogenesis. Brain 129(Pt 5):1194–1200. doi:10.1093/brain/awl041

    PubMed  Google Scholar 

  122. Winner B, Geyer M, Couillard-Despres S, Aigner R, Bogdahn U, Aigner L, Kuhn G, Winkler J (2006) Striatal deafferentation increases dopaminergic neurogenesis in the adult olfactory bulb. Exp Neurol 197(1):113–121. doi:10.1016/j.expneurol.2005.08.028

    CAS  PubMed  Google Scholar 

  123. Baker SA, Baker KA, Hagg T (2004) Dopaminergic nigrostriatal projections regulate neural precursor proliferation in the adult mouse subventricular zone. Eur J Neurosci 20(2):575–579. doi:10.1111/j.1460-9568.2004.03486.x

    PubMed  Google Scholar 

  124. Sui Y, Horne MK, Stanic D (2012) Reduced proliferation in the adult mouse subventricular zone increases survival of olfactory bulb interneurons. PLoS ONE 7(2):e31549. doi:10.1371/journal.pone.0031549

    CAS  PubMed Central  PubMed  Google Scholar 

  125. Aponso PM, Faull RL, Connor B (2008) Increased progenitor cell proliferation and astrogenesis in the partial progressive 6-hydroxydopamine model of Parkinson’s disease. Neuroscience 151(4):1142–1153. doi:10.1016/j.neuroscience.2007.11.036

    CAS  PubMed  Google Scholar 

  126. Arias-Carrion O, Hernandez-Lopez S, Ibanez-Sandoval O, Bargas J, Hernandez-Cruz A, Drucker-Colin R (2006) Neuronal precursors within the adult rat subventricular zone differentiate into dopaminergic neurons after substantia nigra lesion and chromaffin cell transplant. J Neurosci Res 84(7):1425–1437. doi:10.1002/jnr.21068

    CAS  PubMed  Google Scholar 

  127. Liu BF, Gao EJ, Zeng XZ, Ji M, Cai Q, Lu Q, Yang H, Xu QY (2006) Proliferation of neural precursors in the subventricular zone after chemical lesions of the nigrostriatal pathway in rat brain. Brain Res 1106(1):30–39. doi:10.1016/j.brainres.2006.05.111

    CAS  PubMed  Google Scholar 

  128. Worlitzer MM, Viel T, Jacobs AH, Schwamborn JC (2013) The majority of newly generated cells in the adult mouse substantia nigra express low levels of Doublecortin, but their proliferation is unaffected by 6-OHDA-induced nigral lesion or Minocycline-mediated inhibition of neuroinflammation. Eur J Neurosci 38(5):2684–2692. doi:10.1111/ejn.12269

    PubMed  Google Scholar 

  129. Gao HM, Kotzbauer PT, Uryu K, Leight S, Trojanowski JQ, Lee VM (2008) Neuroinflammation and oxidation/nitration of alpha-synuclein linked to dopaminergic neurodegeneration. J Neurosci 28(30):7687–7698. doi:10.1523/jneurosci.0143-07.2008

    CAS  PubMed Central  PubMed  Google Scholar 

  130. Machado A, Herrera AJ, Venero JL, Santiago M, de Pablos RM, Villaran RF, Espinosa-Oliva AM, Arguelles S, Sarmiento M, Delgado-Cortes MJ, Maurino R, Cano J (2011) Inflammatory animal model for Parkinson’s disease: the intranigral injection of LPS induced the inflammatory process along with the selective degeneration of nigrostriatal dopaminergic neurons. ISRN Neurol 2011:476158. doi:10.5402/2011/476158

    CAS  PubMed Central  PubMed  Google Scholar 

  131. McGeer PL, Itagaki S, Boyes BE, McGeer EG (1988) Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinson’s and Alzheimer’s disease brains. Neurology 38(8):1285–1291

    CAS  PubMed  Google Scholar 

  132. Cicchetti F, Brownell AL, Williams K, Chen YI, Livni E, Isacson O (2002) Neuroinflammation of the nigrostriatal pathway during progressive 6-OHDA dopamine degeneration in rats monitored by immunohistochemistry and PET imaging. Eur J Neurosci 15(6):991–998

    CAS  PubMed  Google Scholar 

  133. Worlitzer MM, Bunk EC, Hemmer K, Schwamborn JC (2012) Anti-inflammatory treatment induced regenerative oligodendrogenesis in parkinsonian mice. Stem Cell Res Ther 3(4):33. doi:10.1186/scrt124

    CAS  PubMed Central  PubMed  Google Scholar 

  134. Vallieres L, Campbell IL, Gage FH, Sawchenko PE (2002) Reduced hippocampal neurogenesis in adult transgenic mice with chronic astrocytic production of interleukin-6. J Neurosci 22(2):486–492

    CAS  PubMed  Google Scholar 

  135. Monje ML, Toda H, Palmer TD (2003) Inflammatory blockade restores adult hippocampal neurogenesis. Science 302(5651):1760–1765. doi:10.1126/science.1088417

    CAS  PubMed  Google Scholar 

  136. Zhang P, Liu Y, Li J, Kang Q, Tian Y, Chen X, Shi Q, Song T (2006) Cell proliferation in ependymal/subventricular zone and nNOS expression following focal cerebral ischemia in adult rats. Neurol Res 28(1):91–96. doi:10.1179/016164106x91942

    PubMed  Google Scholar 

  137. Das S, Dutta K, Kumawat KL, Ghoshal A, Adhya D, Basu A (2011) Abrogated inflammatory response promotes neurogenesis in a murine model of Japanese encephalitis. PLoS ONE 6(3):e17225. doi:10.1371/journal.pone.0017225

    CAS  PubMed Central  PubMed  Google Scholar 

  138. Hoehn BD, Palmer TD, Steinberg GK (2005) Neurogenesis in rats after focal cerebral ischemia is enhanced by indomethacin. Stroke 36(12):2718–2724. doi:10.1161/01.STR.0000190020.30282.cc

    CAS  PubMed  Google Scholar 

  139. Ng SY, Semple BD, Morganti-Kossmann MC, Bye N (2012) Attenuation of microglial activation with minocycline is not associated with changes in neurogenesis after focal traumatic brain injury in adult mice. J Neurotrauma 29(7):1410–1425. doi:10.1089/neu.2011.2188

    PubMed  Google Scholar 

  140. Cardona AE, Pioro EP, Sasse ME, Kostenko V, Cardona SM, Dijkstra IM, Huang D, Kidd G, Dombrowski S, Dutta R, Lee JC, Cook DN, Jung S, Lira SA, Littman DR, Ransohoff RM (2006) Control of microglial neurotoxicity by the fractalkine receptor. Nat Neurosci 9(7):917–924. doi:10.1038/nn1715

    CAS  PubMed  Google Scholar 

  141. Bachstetter AD, Morganti JM, Jernberg J, Schlunk A, Mitchell SH, Brewster KW, Hudson CE, Cole MJ, Harrison JK, Bickford PC, Gemma C (2011) Fractalkine and CX 3 CR1 regulate hippocampal neurogenesis in adult and aged rats. Neurobiol Aging 32(11):2030–2044. doi:10.1016/j.neurobiolaging.2009.11.022

    CAS  PubMed Central  PubMed  Google Scholar 

  142. Coronas V, Bantubungi K, Fombonne J, Krantic S, Schiffmann SN, Roger M (2004) Dopamine D3 receptor stimulation promotes the proliferation of cells derived from the post-natal subventricular zone. J Neurochem 91(6):1292–1301. doi:10.1111/j.1471-4159.2004.02823.x

    CAS  PubMed  Google Scholar 

  143. Kippin TE, Kapur S, van der Kooy D (2005) Dopamine specifically inhibits forebrain neural stem cell proliferation, suggesting a novel effect of antipsychotic drugs. J Neurosci 25(24):5815–5823. doi:10.1523/jneurosci.1120-05.2005

    CAS  PubMed  Google Scholar 

  144. Diaz J, Ridray S, Mignon V, Griffon N, Schwartz JC, Sokoloff P (1997) Selective expression of dopamine D3 receptor mRNA in proliferative zones during embryonic development of the rat brain. J Neurosci 17(11):4282–4292

    CAS  PubMed  Google Scholar 

  145. Kim Y, Wang WZ, Comte I, Pastrana E, Tran PB, Brown J, Miller RJ, Doetsch F, Molnar Z, Szele FG (2010) Dopamine stimulation of postnatal murine subventricular zone neurogenesis via the D3 receptor. J Neurochem 114(3):750–760. doi:10.1111/j.1471-4159.2010.06799.x

    CAS  PubMed Central  PubMed  Google Scholar 

  146. Winner B, Desplats P, Hagl C, Klucken J, Aigner R, Ploetz S, Laemke J, Karl A, Aigner L, Masliah E, Buerger E, Winkler J (2009) Dopamine receptor activation promotes adult neurogenesis in an acute Parkinson model. Exp Neurol 219(2):543–552. doi:10.1016/j.expneurol.2009.07.013

    CAS  PubMed  Google Scholar 

  147. Van Kampen JM, Robertson HA (2005) A possible role for dopamine D3 receptor stimulation in the induction of neurogenesis in the adult rat substantia nigra. Neuroscience 136(2):381–386. doi:10.1016/j.neuroscience.2005.07.054

    PubMed  Google Scholar 

  148. Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, Dutra A, Pike B, Root H, Rubenstein J, Boyer R, Stenroos ES, Chandrasekharappa S, Athanassiadou A, Papapetropoulos T, Johnson WG, Lazzarini AM, Duvoisin RC, Di Iorio G, Golbe LI, Nussbaum RL (1997) Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science 276(5321):2045–2047

    CAS  PubMed  Google Scholar 

  149. Kruger R, Kuhn W, Muller T, Woitalla D, Graeber M, Kosel S, Przuntek H, Epplen JT, Schols L, Riess O (1998) Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson’s disease. Nat Genet 18(2):106–108. doi:10.1038/ng0298-106

    CAS  PubMed  Google Scholar 

  150. Zarranz JJ, Alegre J, Gomez-Esteban JC, Lezcano E, Ros R, Ampuero I, Vidal L, Hoenicka J, Rodriguez O, Atares B, Llorens V, Gomez Tortosa E, del Ser T, Munoz DG, de Yebenes JG (2004) The new mutation, E46K, of alpha-synuclein causes Parkinson and Lewy body dementia. Ann Neurol 55(2):164–173. doi:10.1002/ana.10795

    CAS  PubMed  Google Scholar 

  151. Ibanez P, Bonnet AM, Debarges B, Lohmann E, Tison F, Pollak P, Agid Y, Durr A, Brice A (2004) Causal relation between alpha-synuclein gene duplication and familial Parkinson’s disease. Lancet 364(9440):1169–1171. doi:10.1016/s0140-6736(04)17104-3

    CAS  PubMed  Google Scholar 

  152. Singleton AB, Farrer M, Johnson J, Singleton A, Hague S, Kachergus J, Hulihan M, Peuralinna T, Dutra A, Nussbaum R, Lincoln S, Crawley A, Hanson M, Maraganore D, Adler C, Cookson MR, Muenter M, Baptista M, Miller D, Blancato J, Hardy J, Gwinn-Hardy K (2003) alpha-Synuclein locus triplication causes Parkinson’s disease. Science 302(5646):841. doi:10.1126/science.1090278

    CAS  PubMed  Google Scholar 

  153. Hoffman-Zacharska D, Koziorowski D, Ross OA, Milewski M, Poznanski J, Jurek M, Wszolek ZK, Soto-Ortolaza A, Slawek J, Janik P, Jamrozik Z, Potulska-Chromik A, Jasinska-Myga B, Opala G, Krygowska-Wajs A, Czyzewski K, Dickson DW, Bal J, Friedman A (2013) Novel A18T and pA29S substitutions in alpha-synuclein may be associated with sporadic Parkinson’s disease. Parkinsonism Relat Disord 19(11):1057–1060. doi:10.1016/j.parkreldis.2013.07.011

    PubMed Central  PubMed  Google Scholar 

  154. Appel-Cresswell S, Vilarino-Guell C, Encarnacion M, Sherman H, Yu I, Shah B, Weir D, Thompson C, Szu-Tu C, Trinh J, Aasly JO, Rajput A, Rajput AH, Jon Stoessl A, Farrer MJ (2013) Alpha-synuclein p. H50Q, a novel pathogenic mutation for Parkinson’s disease. Mov Disord 28(6):811–813. doi:10.1002/mds.25421

    CAS  PubMed  Google Scholar 

  155. Lesage S, Anheim M, Letournel F, Bousset L, Honore A, Rozas N, Pieri L, Madiona K, Durr A, Melki R, Verny C, Brice A (2013) G51D alpha-synuclein mutation causes a novel Parkinsonian-pyramidal syndrome. Ann Neurol 73(4):459–471. doi:10.1002/ana.23894

    CAS  PubMed  Google Scholar 

  156. Vekrellis K, Rideout HJ, Stefanis L (2004) Neurobiology of alpha-synuclein. Mol Neurobiol 30(1):1–21. doi:10.1385/MN:30:1:001

    CAS  PubMed  Google Scholar 

  157. Bendor JT, Logan TP, Edwards RH (2013) The function of alpha-synuclein. Neuron 79(6):1044–1066. doi:10.1016/j.neuron.2013.09.004

    CAS  PubMed  Google Scholar 

  158. Perez RG, Waymire JC, Lin E, Liu JJ, Guo F, Zigmond MJ (2002) A role for alpha-synuclein in the regulation of dopamine biosynthesis. J Neurosci 22(8):3090–3099 (pii: 20026307 22/8/3090)

    CAS  PubMed  Google Scholar 

  159. Clayton DF, George JM (1999) Synucleins in synaptic plasticity and neurodegenerative disorders. J Neurosci Res 58(1):120–129. doi:10.1002/(SICI)1097-4547(19991001)58:1<120:AID-JNR12>3.0.CO;2-E

    CAS  PubMed  Google Scholar 

  160. George JM, Jin H, Woods WS, Clayton DF (1995) Characterization of a novel protein regulated during the critical period for song learning in the zebra finch. Neuron 15(2):361–372 (pii: 0896-6273(95)90040-3)

    CAS  PubMed  Google Scholar 

  161. Cabin DE, Shimazu K, Murphy D, Cole NB, Gottschalk W, McIlwain KL, Orrison B, Chen A, Ellis CE, Paylor R, Lu B, Nussbaum RL (2002) Synaptic vesicle depletion correlates with attenuated synaptic responses to prolonged repetitive stimulation in mice lacking alpha-synuclein. J Neurosci 22(20):8797–8807 (pii: 22/20/8797)

    CAS  PubMed  Google Scholar 

  162. Murphy DD, Rueter SM, Trojanowski JQ, Lee VM (2000) Synucleins are developmentally expressed, and alpha-synuclein regulates the size of the presynaptic vesicular pool in primary hippocampal neurons. J Neurosci 20(9):3214–3220

    CAS  PubMed  Google Scholar 

  163. Abeliovich A, Schmitz Y, Farinas I, Choi-Lundberg D, Ho WH, Castillo PE, Shinsky N, Verdugo JM, Armanini M, Ryan A, Hynes M, Phillips H, Sulzer D, Rosenthal A (2000) Mice lacking alpha-synuclein display functional deficits in the nigrostriatal dopamine system. Neuron 25(1):239–252

    CAS  PubMed  Google Scholar 

  164. Chandra S, Gallardo G, Fernandez-Chacon R, Schluter OM, Sudhof TC (2005) Alpha-synuclein cooperates with CSPalpha in preventing neurodegeneration. Cell 123(3):383–396. doi:10.1016/j.cell.2005.09.028

    CAS  PubMed  Google Scholar 

  165. Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M (1997) Alpha-synuclein in Lewy bodies. Nature 388(6645):839–840. doi:10.1038/42166

    CAS  PubMed  Google Scholar 

  166. Takeda A, Mallory M, Sundsmo M, Honer W, Hansen L, Masliah E (1998) Abnormal accumulation of NACP/alpha-synuclein in neurodegenerative disorders. Am J Pathol 152(2):367–372

    CAS  PubMed Central  PubMed  Google Scholar 

  167. Olanow CW, Brundin P (2013) Parkinson’s disease and alpha synuclein: is Parkinson’s disease a prion-like disorder? Mov Disord 28(1):31–40. doi:10.1002/mds.25373

    CAS  PubMed  Google Scholar 

  168. Winner B, Lie DC, Rockenstein E, Aigner R, Aigner L, Masliah E, Kuhn HG, Winkler J (2004) Human wild-type alpha-synuclein impairs neurogenesis. J Neuropathol Exp Neurol 63(11):1155–1166

    CAS  PubMed  Google Scholar 

  169. Tani M, Hayakawa H, Yasuda T, Nihira T, Hattori N, Mizuno Y, Mochizuki H (2010) Ectopic expression of alpha-synuclein affects the migration of neural stem cells in mouse subventricular zone. J Neurochem 115(4):854–863. doi:10.1111/j.1471-4159.2010.06727.x

    CAS  PubMed  Google Scholar 

  170. May VE, Nuber S, Marxreiter F, Riess O, Winner B, Winkler J (2012) Impaired olfactory bulb neurogenesis depends on the presence of human wild-type alpha-synuclein. Neuroscience 222:343–355. doi:10.1016/j.neuroscience.2012.07.001

    CAS  PubMed  Google Scholar 

  171. Cabeza-Arvelaiz Y, Fleming SM, Richter F, Masliah E, Chesselet MF, Schiestl RH (2011) Analysis of striatal transcriptome in mice overexpressing human wild-type alpha-synuclein supports synaptic dysfunction and suggests mechanisms of neuroprotection for striatal neurons. Mol Neurodegener 6:83. doi:10.1186/1750-1326-6-83

    CAS  PubMed Central  PubMed  Google Scholar 

  172. Crews L, Mizuno H, Desplats P, Rockenstein E, Adame A, Patrick C, Winner B, Winkler J, Masliah E (2008) Alpha-synuclein alters Notch-1 expression and neurogenesis in mouse embryonic stem cells and in the hippocampus of transgenic mice. J Neurosci 28(16):4250–4260. doi:10.1523/jneurosci.0066-08.2008

    CAS  PubMed Central  PubMed  Google Scholar 

  173. Desplats P, Spencer B, Crews L, Pathel P, Morvinski-Friedmann D, Kosberg K, Roberts S, Patrick C, Winner B, Winkler J, Masliah E (2012) Alpha-Synuclein induces alterations in adult neurogenesis in Parkinson disease models via p53-mediated repression of Notch1. J Biol Chem 287(38):31691–31702. doi:10.1074/jbc.M112.354522

    CAS  PubMed Central  PubMed  Google Scholar 

  174. Winner B, Rockenstein E, Lie DC, Aigner R, Mante M, Bogdahn U, Couillard-Despres S, Masliah E, Winkler J (2008) Mutant alpha-synuclein exacerbates age-related decrease of neurogenesis. Neurobiol Aging 29(6):913–925. doi:10.1016/j.neurobiolaging.2006.12.016

    CAS  PubMed Central  PubMed  Google Scholar 

  175. Marxreiter F, Nuber S, Kandasamy M, Klucken J, Aigner R, Burgmayer R, Couillard-Despres S, Riess O, Winkler J, Winner B (2009) Changes in adult olfactory bulb neurogenesis in mice expressing the A30P mutant form of alpha-synuclein. Eur J Neurosci 29(5):879–890. doi:10.1111/j.1460-9568.2009.06641.x

    PubMed  Google Scholar 

  176. Marxreiter F, Ettle B, May VE, Esmer H, Patrick C, Kragh CL, Klucken J, Winner B, Riess O, Winkler J, Masliah E, Nuber S (2013) Glial A30P alpha-synuclein pathology segregates neurogenesis from anxiety-related behavior in conditional transgenic mice. Neurobiol Dis 59:38–51. doi:10.1016/j.nbd.2013.07.004

    CAS  PubMed  Google Scholar 

  177. Tofaris GK, Garcia Reitbock P, Humby T, Lambourne SL, O’Connell M, Ghetti B, Gossage H, Emson PC, Wilkinson LS, Goedert M, Spillantini MG (2006) Pathological changes in dopaminergic nerve cells of the substantia nigra and olfactory bulb in mice transgenic for truncated human alpha-synuclein(1-120): implications for Lewy body disorders. J Neurosci 26(15):3942–3950. doi:10.1523/JNEUROSCI.4965-05.2006

    CAS  PubMed  Google Scholar 

  178. Garcia-Reitbock P, Anichtchik O, Bellucci A, Iovino M, Ballini C, Fineberg E, Ghetti B, Della Corte L, Spano P, Tofaris GK, Goedert M, Spillantini MG (2010) SNARE protein redistribution and synaptic failure in a transgenic mouse model of Parkinson’s disease. Brain 133(Pt 7):2032–2044. doi:10.1093/brain/awq132

    PubMed Central  PubMed  Google Scholar 

  179. Fleming SM, Tetreault NA, Mulligan CK, Hutson CB, Masliah E, Chesselet MF (2008) Olfactory deficits in mice overexpressing human wildtype alpha-synuclein. Eur J Neurosci 28(2):247–256. doi:10.1111/j.1460-9568.2008.06346.x

    PubMed Central  PubMed  Google Scholar 

  180. Petit GH, Berkovich E, Hickery M, Kallunki P, Fog K, Fitzer-Attas C, Brundin P (2013) Rasagiline ameliorates olfactory deficits in an alpha-synuclein mouse model of Parkinson’s disease. PLoS ONE 8(4):e60691. doi:10.1371/journal.pone.0060691

    CAS  PubMed Central  PubMed  Google Scholar 

  181. Hansen C, Bjorklund T, Petit GH, Lundblad M, Murmu RP, Brundin P, Li JY (2013) A novel alpha-synuclein-GFP mouse model displays progressive motor impairment, olfactory dysfunction and accumulation of alpha-synuclein-GFP. Neurobiol Dis 56:145–155. doi:10.1016/j.nbd.2013.04.017

    CAS  PubMed  Google Scholar 

  182. Neuner J, Filser S, Michalakis S, Biel M, Herms J (2014) A30P alpha-Synuclein interferes with the stable integration of adult-born neurons into the olfactory network. Sci Rep 4:3931. doi:10.1038/srep03931

    PubMed Central  PubMed  Google Scholar 

  183. Neuner J, Ovsepian SV, Dorostkar M, Filser S, Gupta A, Michalakis S, Biel M, Herms J (2014) Pathological alpha-synuclein impairs adult-born granule cell development and functional integration in the olfactory bulb. Nat Commun 5:3915. doi:10.1038/ncomms4915

    PubMed Central  PubMed  Google Scholar 

  184. Winner B, Regensburger M, Schreglmann S, Boyer L, Prots I, Rockenstein E, Mante M, Zhao C, Winkler J, Masliah E, Gage FH (2012) Role of alpha-synuclein in adult neurogenesis and neuronal maturation in the dentate gyrus. J Neurosci 32(47):16906–16916. doi:10.1523/JNEUROSCI.2723-12.2012

    CAS  PubMed  Google Scholar 

  185. Kumari U, Tan EK (2009) LRRK2 in Parkinson’s disease: genetic and clinical studies from patients. FEBS J 276(22):6455–6463. doi:10.1111/j.1742-4658.2009.07344.x

    CAS  PubMed  Google Scholar 

  186. Healy DG, Falchi M, O’Sullivan SS, Bonifati V, Durr A, Bressman S, Brice A, Aasly J, Zabetian CP, Goldwurm S, Ferreira JJ, Tolosa E, Kay DM, Klein C, Williams DR, Marras C, Lang AE, Wszolek ZK, Berciano J, Schapira AH, Lynch T, Bhatia KP, Gasser T, Lees AJ, Wood NW (2008) Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson’s disease: a case–control study. Lancet Neurol 7(7):583–590. doi:10.1016/s1474-4422(08)70117-0

    CAS  PubMed Central  PubMed  Google Scholar 

  187. Zimprich A, Biskup S, Leitner P, Lichtner P, Farrer M, Lincoln S, Kachergus J, Hulihan M, Uitti RJ, Calne DB, Stoessl AJ, Pfeiffer RF, Patenge N, Carbajal IC, Vieregge P, Asmus F, Muller-Myhsok B, Dickson DW, Meitinger T, Strom TM, Wszolek ZK, Gasser T (2004) Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron 44(4):601–607. doi:10.1016/j.neuron.2004.11.005

    CAS  PubMed  Google Scholar 

  188. Paisan-Ruiz C, Jain S, Evans EW, Gilks WP, Simon J, van der Brug M, Lopez de Munain A, Aparicio S, Gil AM, Khan N, Johnson J, Martinez JR, Nicholl D, Carrera IM, Pena AS, de Silva R, Lees A, Marti-Masso JF, Perez-Tur J, Wood NW, Singleton AB (2004) Cloning of the gene containing mutations that cause PARK8-linked Parkinson’s disease. Neuron 44(4):595–600. doi:10.1016/j.neuron.2004.10.023

    CAS  PubMed  Google Scholar 

  189. Farrer M, Stone J, Mata IF, Lincoln S, Kachergus J, Hulihan M, Strain KJ, Maraganore DM (2005) LRRK2 mutations in Parkinson disease. Neurology 65(5):738–740. doi:10.1212/01.wnl.0000169023.51764.b0

    CAS  PubMed  Google Scholar 

  190. Mata IF, Taylor JP, Kachergus J, Hulihan M, Huerta C, Lahoz C, Blazquez M, Guisasola LM, Salvador C, Ribacoba R, Martinez C, Farrer M, Alvarez V (2005) LRRK2 R1441G in Spanish patients with Parkinson’s disease. Neurosci Lett 382(3):309–311. doi:10.1016/j.neulet.2005.03.033

    CAS  PubMed  Google Scholar 

  191. Kachergus J, Mata IF, Hulihan M, Taylor JP, Lincoln S, Aasly J, Gibson JM, Ross OA, Lynch T, Wiley J, Payami H, Nutt J, Maraganore DM, Czyzewski K, Styczynska M, Wszolek ZK, Farrer MJ, Toft M (2005) Identification of a novel LRRK2 mutation linked to autosomal dominant parkinsonism: evidence of a common founder across European populations. Am J Hum Genet 76(4):672–680. doi:10.1086/429256

    CAS  PubMed Central  PubMed  Google Scholar 

  192. Mata IF, Wedemeyer WJ, Farrer MJ, Taylor JP, Gallo KA (2006) LRRK2 in Parkinson’s disease: protein domains and functional insights. Trends Neurosci 29(5):286–293. doi:10.1016/j.tins.2006.03.006

    CAS  PubMed  Google Scholar 

  193. West AB, Moore DJ, Biskup S, Bugayenko A, Smith WW, Ross CA, Dawson VL, Dawson TM (2005) Parkinson’s disease-associated mutations in leucine-rich repeat kinase 2 augment kinase activity. Proc Natl Acad Sci USA 102(46):16842–16847. doi:10.1073/pnas.0507360102

    CAS  PubMed Central  PubMed  Google Scholar 

  194. Li X, Tan YC, Poulose S, Olanow CW, Huang XY, Yue Z (2007) Leucine-rich repeat kinase 2 (LRRK2)/PARK8 possesses GTPase activity that is altered in familial Parkinson’s disease R1441C/G mutants. J Neurochem 103(1):238–247. doi:10.1111/j.1471-4159.2007.04743.x

    CAS  PubMed Central  PubMed  Google Scholar 

  195. Melrose HL, Kent CB, Taylor JP, Dachsel JC, Hinkle KM, Lincoln SJ, Mok SS, Culvenor JG, Masters CL, Tyndall GM, Bass DI, Ahmed Z, Andorfer CA, Ross OA, Wszolek ZK, Delldonne A, Dickson DW, Farrer MJ (2007) A comparative analysis of leucine-rich repeat kinase 2 (Lrrk2) expression in mouse brain and Lewy body disease. Neuroscience 147(4):1047–1058. doi:10.1016/j.neuroscience.2007.05.027

    CAS  PubMed  Google Scholar 

  196. Andres-Mateos E, Mejias R, Sasaki M, Li X, Lin BM, Biskup S, Zhang L, Banerjee R, Thomas B, Yang L, Liu G, Beal MF, Huso DL, Dawson TM, Dawson VL (2009) Unexpected lack of hypersensitivity in LRRK2 knock-out mice to MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). J Neurosci 29(50):15846–15850. doi:10.1523/jneurosci.4357-09.2009

    CAS  PubMed Central  PubMed  Google Scholar 

  197. Bahnassawy L, Nicklas S, Palm T, Menzl I, Birzele F, Gillardon F, Schwamborn JC (2013) The Parkinson’s disease-associated LRRK2 mutation R1441G inhibits neuronal differentiation of neural stem cells. Stem Cells Dev. doi:10.1089/scd.2013.0163

    PubMed  Google Scholar 

  198. Schulz C, Paus M, Frey K, Schmid R, Kohl Z, Mennerich D, Winkler J, Gillardon F (2011) Leucine-rich repeat kinase 2 modulates retinoic acid-induced neuronal differentiation of murine embryonic stem cells. PLoS ONE 6(6):e20820. doi:10.1371/journal.pone.0020820

    CAS  PubMed Central  PubMed  Google Scholar 

  199. Milosevic J, Schwarz SC, Ogunlade V, Meyer AK, Storch A, Schwarz J (2009) Emerging role of LRRK2 in human neural progenitor cell cycle progression, survival and differentiation. Mol Neurodegener 4:25. doi:10.1186/1750-1326-4-25

    PubMed Central  PubMed  Google Scholar 

  200. Liu GH, Qu J, Suzuki K, Nivet E, Li M, Montserrat N, Yi F, Xu X, Ruiz S, Zhang W, Wagner U, Kim A, Ren B, Li Y, Goebl A, Kim J, Soligalla RD, Dubova I, Thompson J, Yates J 3rd, Esteban CR, Sancho-Martinez I, Izpisua Belmonte JC (2012) Progressive degeneration of human neural stem cells caused by pathogenic LRRK2. Nature 491(7425):603–607. doi:10.1038/nature11557

    CAS  PubMed Central  PubMed  Google Scholar 

  201. Meister G (2013) Argonaute proteins: functional insights and emerging roles. Nat Rev Genet 14(7):447–459. doi:10.1038/nrg3462

    CAS  PubMed  Google Scholar 

  202. Bernstein E, Caudy AA, Hammond SM, Hannon GJ (2001) Role for a bidentate ribonuclease in the initiation step of RNA interference. Nature 409(6818):363–366. doi:10.1038/35053110

    CAS  PubMed  Google Scholar 

  203. Gu S, Kay MA (2010) How do miRNAs mediate translational repression? Silence 1(1):11. doi:10.1186/1758-907x-1-11

    PubMed Central  PubMed  Google Scholar 

  204. Follert P, Cremer H, Beclin C (2014) MicroRNAs in brain development and function: a matter of flexibility and stability. Front Mol Neurosci 7:5. doi:10.3389/fnmol.2014.00005

    PubMed Central  PubMed  Google Scholar 

  205. Nowak JS, Michlewski G (2013) miRNAs in development and pathogenesis of the nervous system. Biochem Soc Trans 41(4):815–820. doi:10.1042/bst20130044

    CAS  PubMed  Google Scholar 

  206. Petri R, Malmevik J, Fasching L, Akerblom M, Jakobsson J (2014) miRNAs in brain development. Exp Cell Res 321(1):84–89. doi:10.1016/j.yexcr.2013.09.022

    CAS  PubMed  Google Scholar 

  207. Palm T, Bahnassawy L, Schwamborn J (2012) MiRNAs and neural stem cells: a team to treat Parkinson’s disease? RNA Biol 9(6):720–730. doi:10.4161/rna.19984

    CAS  PubMed  Google Scholar 

  208. Wang S, Xu J, Ye R, Wang J, Chen Z, Huang R, Peng Q, Xu Y, Cai X (2014) Emerging roles of microRNAs in neural stem cells. Curr Stem Cell Res Ther 9(3):234–243

    CAS  PubMed  Google Scholar 

  209. Gehrke S, Imai Y, Sokol N, Lu B (2010) Pathogenic LRRK2 negatively regulates microRNA-mediated translational repression. Nature 466(7306):637–641. doi:10.1038/nature09191

    CAS  PubMed Central  PubMed  Google Scholar 

  210. Berwick DC, Harvey K (2013) LRRK2: an eminence grise of Wnt-mediated neurogenesis? Front Cell Neurosci 7:82. doi:10.3389/fncel.2013.00082

    CAS  PubMed Central  PubMed  Google Scholar 

  211. Rawal N, Corti O, Sacchetti P, Ardilla-Osorio H, Sehat B, Brice A, Arenas E (2009) Parkin protects dopaminergic neurons from excessive Wnt/beta-catenin signaling. Biochem Biophys Res Commun 388(3):473–478. doi:10.1016/j.bbrc.2009.07.014

    CAS  PubMed  Google Scholar 

  212. Vilarino-Guell C, Wider C, Ross OA, Dachsel JC, Kachergus JM, Lincoln SJ, Soto-Ortolaza AI, Cobb SA, Wilhoite GJ, Bacon JA, Behrouz B, Melrose HL, Hentati E, Puschmann A, Evans DM, Conibear E, Wasserman WW, Aasly JO, Burkhard PR, Djaldetti R, Ghika J, Hentati F, Krygowska-Wajs A, Lynch T, Melamed E, Rajput A, Rajput AH, Solida A, Wu RM, Uitti RJ, Wszolek ZK, Vingerhoets F, Farrer MJ (2011) VPS35 mutations in Parkinson disease. Am J Hum Genet 89(1):162–167. doi:10.1016/j.ajhg.2011.06.001

    PubMed Central  PubMed  Google Scholar 

  213. Zimprich A, Benet-Pages A, Struhal W, Graf E, Eck SH, Offman MN, Haubenberger D, Spielberger S, Schulte EC, Lichtner P, Rossle SC, Klopp N, Wolf E, Seppi K, Pirker W, Presslauer S, Mollenhauer B, Katzenschlager R, Foki T, Hotzy C, Reinthaler E, Harutyunyan A, Kralovics R, Peters A, Zimprich F, Brucke T, Poewe W, Auff E, Trenkwalder C, Rost B, Ransmayr G, Winkelmann J, Meitinger T, Strom TM (2011) A mutation in VPS35, encoding a subunit of the retromer complex, causes late-onset Parkinson disease. Am J Hum Genet 89(1):168–175. doi:10.1016/j.ajhg.2011.06.008

    CAS  PubMed Central  PubMed  Google Scholar 

  214. Sharma M, Ioannidis JP, Aasly JO, Annesi G, Brice A, Bertram L, Bozi M, Barcikowska M, Crosiers D, Clarke CE, Facheris MF, Farrer M, Garraux G, Gispert S, Auburger G, Vilarino-Guell C, Hadjigeorgiou GM, Hicks AA, Hattori N, Jeon BS, Jamrozik Z, Krygowska-Wajs A, Lesage S, Lill CM, Lin JJ, Lynch T, Lichtner P, Lang AE, Libioulle C, Murata M, Mok V, Jasinska-Myga B, Mellick GD, Morrison KE, Meitnger T, Zimprich A, Opala G, Pramstaller PP, Pichler I, Park SS, Quattrone A, Rogaeva E, Ross OA, Stefanis L, Stockton JD, Satake W, Silburn PA, Strom TM, Theuns J, Tan EK, Toda T, Tomiyama H, Uitti RJ, Van Broeckhoven C, Wirdefeldt K, Wszolek Z, Xiromerisiou G, Yomono HS, Yueh KC, Zhao Y, Gasser T, Maraganore D, Kruger R (2012) A multi-centre clinico-genetic analysis of the VPS35 gene in Parkinson disease indicates reduced penetrance for disease-associated variants. J Med Genet 49(11):721–726. doi:10.1136/jmedgenet-2012-101155

    CAS  PubMed Central  PubMed  Google Scholar 

  215. Ando M, Funayama M, Li Y, Kashihara K, Murakami Y, Ishizu N, Toyoda C, Noguchi K, Hashimoto T, Nakano N, Sasaki R, Kokubo Y, Kuzuhara S, Ogaki K, Yamashita C, Yoshino H, Hatano T, Tomiyama H, Hattori N (2012) VPS35 mutation in Japanese patients with typical Parkinson’s disease. Mov Disord 27(11):1413–1417. doi:10.1002/mds.25145

    CAS  PubMed  Google Scholar 

  216. Kumar KR, Weissbach A, Heldmann M, Kasten M, Tunc S, Sue CM, Svetel M, Kostic VS, Segura-Aguilar J, Ramirez A, Simon DK, Vieregge P, Munte TF, Hagenah J, Klein C, Lohmann K (2012) Frequency of the D620N mutation in VPS35 in Parkinson disease. Arch Neurol 69(10):1360–1364. doi:10.1001/archneurol.2011.3367

    PubMed  Google Scholar 

  217. Lesage S, Condroyer C, Klebe S, Honore A, Tison F, Brefel-Courbon C, Durr A, Brice A (2012) Identification of VPS35 mutations replicated in French families with Parkinson disease. Neurology 78(18):1449–1450. doi:10.1212/WNL.0b013e318253d5f2

    CAS  PubMed  Google Scholar 

  218. MacLeod DA, Rhinn H, Kuwahara T, Zolin A, Di Paolo G, McCabe BD, Marder KS, Honig LS, Clark LN, Small SA, Abeliovich A (2013) RAB7L1 interacts with LRRK2 to modify intraneuronal protein sorting and Parkinson’s disease risk. Neuron 77(3):425–439. doi:10.1016/j.neuron.2012.11.033

    CAS  PubMed Central  PubMed  Google Scholar 

  219. McGough IJ, Cullen PJ (2011) Recent advances in retromer biology. Traffic 12(8):963–971. doi:10.1111/j.1600-0854.2011.01201.x

    CAS  PubMed  Google Scholar 

  220. Seaman MN (2005) Recycle your receptors with retromer. Trends Cell Biol 15(2):68–75. doi:10.1016/j.tcb.2004.12.004

    CAS  PubMed  Google Scholar 

  221. Bonifacino JS, Hurley JH (2008) Retromer. Curr Opin Cell Biol 20(4):427–436. doi:10.1016/j.ceb.2008.03.009

    CAS  PubMed Central  PubMed  Google Scholar 

  222. Zavodszky E, Seaman MN, Moreau K, Jimenez-Sanchez M, Breusegem SY, Harbour ME, Rubinsztein DC (2014) Mutation in VPS35 associated with Parkinson’s disease impairs WASH complex association and inhibits autophagy. Nat Commun 5:3828. doi:10.1038/ncomms4828

    PubMed Central  PubMed  Google Scholar 

  223. Braschi E, Goyon V, Zunino R, Mohanty A, Xu L, McBride HM (2010) Vps35 mediates vesicle transport between the mitochondria and peroxisomes. Curr Biol 20(14):1310–1315. doi:10.1016/j.cub.2010.05.066

    CAS  PubMed  Google Scholar 

  224. Tabuchi M, Yanatori I, Kawai Y, Kishi F (2010) Retromer-mediated direct sorting is required for proper endosomal recycling of the mammalian iron transporter DMT1. J Cell Sci 123(Pt 5):756–766. doi:10.1242/jcs.060574

    CAS  PubMed  Google Scholar 

  225. Jiang H, Song N, Xu H, Zhang S, Wang J, Xie J (2010) Up-regulation of divalent metal transporter 1 in 6-hydroxydopamine intoxication is IRE/IRP dependent. Cell Res 20(3):345–356. doi:10.1038/cr.2010.20

    CAS  PubMed  Google Scholar 

  226. Belenkaya TY, Wu Y, Tang X, Zhou B, Cheng L, Sharma YV, Yan D, Selva EM, Lin X (2008) The retromer complex influences Wnt secretion by recycling wntless from endosomes to the trans-Golgi network. Dev Cell 14(1):120–131. doi:10.1016/j.devcel.2007.12.003

    CAS  PubMed  Google Scholar 

  227. Coudreuse DY, Roel G, Betist MC, Destree O, Korswagen HC (2006) Wnt gradient formation requires retromer function in Wnt-producing cells. Science 312(5775):921–924. doi:10.1126/science.1124856

    CAS  PubMed  Google Scholar 

  228. George A, Leahy H, Zhou J, Morin PJ (2007) The vacuolar-ATPase inhibitor bafilomycin and mutant VPS35 inhibit canonical Wnt signaling. Neurobiol Dis 26(1):125–133. doi:10.1016/j.nbd.2006.12.004

    CAS  PubMed  Google Scholar 

  229. Dun Y, Li G, Yang Y, Xiong Z, Feng M, Wang M, Zhang Y, Xiang J, Ma R (2012) Inhibition of the canonical Wnt pathway by Dickkopf-1 contributes to the neurodegeneration in 6-OHDA-lesioned rats. Neurosci Lett 525(2):83–88. doi:10.1016/j.neulet.2012.07.030

    CAS  PubMed  Google Scholar 

  230. Ohnuki T, Nakamura A, Okuyama S, Nakamura S (2010) Gene expression profiling in progressively MPTP-lesioned macaques reveals molecular pathways associated with sporadic Parkinson’s disease. Brain Res 1346:26–42. doi:10.1016/j.brainres.2010.05.066

    CAS  PubMed  Google Scholar 

  231. Wen L, Tang FL, Hong Y, Luo SW, Wang CL, He W, Shen C, Jung JU, Xiong F, Lee DH, Zhang QG, Brann D, Kim TW, Yan R, Mei L, Xiong WC (2011) VPS35 haploinsufficiency increases Alzheimer’s disease neuropathology. J Cell Biol 195(5):765–779. doi:10.1083/jcb.201105109

    CAS  PubMed Central  PubMed  Google Scholar 

  232. de Groot RE, Farin HF, Macurkova M, van Es JH, Clevers HC, Korswagen HC (2013) Retromer dependent recycling of the Wnt secretion factor Wls is dispensable for stem cell maintenance in the mammalian intestinal epithelium. PLoS ONE 8(10):e76971. doi:10.1371/journal.pone.0076971

    PubMed Central  PubMed  Google Scholar 

  233. Komatsu M, Waguri S, Chiba T, Murata S, Iwata J, Tanida I, Ueno T, Koike M, Uchiyama Y, Kominami E, Tanaka K (2006) Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 441(7095):880–884. doi:10.1038/nature04723

    CAS  PubMed  Google Scholar 

  234. Hara T, Nakamura K, Matsui M, Yamamoto A, Nakahara Y, Suzuki-Migishima R, Yokoyama M, Mishima K, Saito I, Okano H, Mizushima N (2006) Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 441(7095):885–889. doi:10.1038/nature04724

    CAS  PubMed  Google Scholar 

  235. Fimia GM, Stoykova A, Romagnoli A, Giunta L, Di Bartolomeo S, Nardacci R, Corazzari M, Fuoco C, Ucar A, Schwartz P, Gruss P, Piacentini M, Chowdhury K, Cecconi F (2007) Ambra1 regulates autophagy and development of the nervous system. Nature 447(7148):1121–1125. doi:10.1038/nature05925

    CAS  PubMed  Google Scholar 

  236. Tomoda T, Bhatt RS, Kuroyanagi H, Shirasawa T, Hatten ME (1999) A mouse serine/threonine kinase homologous to C. elegans UNC51 functions in parallel fiber formation of cerebellar granule neurons. Neuron 24(4):833–846

    CAS  PubMed  Google Scholar 

  237. Vazquez P, Arroba AI, Cecconi F, de la Rosa EJ, Boya P, de Pablo F (2012) Atg5 and Ambra1 differentially modulate neurogenesis in neural stem cells. Autophagy 8(2):187–199. doi:10.4161/auto.8.2.18535

    CAS  PubMed  Google Scholar 

  238. Zhao Y, Huang Q, Yang J, Lou M, Wang A, Dong J, Qin Z, Zhang T (2010) Autophagy impairment inhibits differentiation of glioma stem/progenitor cells. Brain Res 1313:250–258. doi:10.1016/j.brainres.2009.12.004

    CAS  PubMed  Google Scholar 

  239. Valente EM, Abou-Sleiman PM, Caputo V, Muqit MM, Harvey K, Gispert S, Ali Z, Del Turco D, Bentivoglio AR, Healy DG, Albanese A, Nussbaum R, Gonzalez-Maldonado R, Deller T, Salvi S, Cortelli P, Gilks WP, Latchman DS, Harvey RJ, Dallapiccola B, Auburger G, Wood NW (2004) Hereditary early-onset Parkinson’s disease caused by mutations in PINK1. Science 304(5674):1158–1160. doi:10.1126/science.1096284

    CAS  PubMed  Google Scholar 

  240. Hatano Y, Li Y, Sato K, Asakawa S, Yamamura Y, Tomiyama H, Yoshino H, Asahina M, Kobayashi S, Hassin-Baer S, Lu CS, Ng AR, Rosales RL, Shimizu N, Toda T, Mizuno Y, Hattori N (2004) Novel PINK1 mutations in early-onset parkinsonism. Ann Neurol 56(3):424–427. doi:10.1002/ana.20251

    CAS  PubMed  Google Scholar 

  241. Ibanez P, Lesage S, Lohmann E, Thobois S, De Michele G, Borg M, Agid Y, Durr A, Brice A (2006) Mutational analysis of the PINK1 gene in early-onset parkinsonism in Europe and North Africa. Brain 129(Pt 3):686–694. doi:10.1093/brain/awl005

    PubMed  Google Scholar 

  242. Kumazawa R, Tomiyama H, Li Y, Imamichi Y, Funayama M, Yoshino H, Yokochi F, Fukusako T, Takehisa Y, Kashihara K, Kondo T, Elibol B, Bostantjopoulou S, Toda T, Takahashi H, Yoshii F, Mizuno Y, Hattori N (2008) Mutation analysis of the PINK1 gene in 391 patients with Parkinson disease. Arch Neurol 65(6):802–808. doi:10.1001/archneur.65.6.802

    PubMed  Google Scholar 

  243. Li Y, Tomiyama H, Sato K, Hatano Y, Yoshino H, Atsumi M, Kitaguchi M, Sasaki S, Kawaguchi S, Miyajima H, Toda T, Mizuno Y, Hattori N (2005) Clinicogenetic study of PINK1 mutations in autosomal recessive early-onset parkinsonism. Neurology 64(11):1955–1957. doi:10.1212/01.wnl.0000164009.36740.4e

    CAS  PubMed  Google Scholar 

  244. Bonifati V, Rohe CF, Breedveld GJ, Fabrizio E, De Mari M, Tassorelli C, Tavella A, Marconi R, Nicholl DJ, Chien HF, Fincati E, Abbruzzese G, Marini P, De Gaetano A, Horstink MW, Maat-Kievit JA, Sampaio C, Antonini A, Stocchi F, Montagna P, Toni V, Guidi M, Dalla Libera A, Tinazzi M, De Pandis F, Fabbrini G, Goldwurm S, de Klein A, Barbosa E, Lopiano L, Martignoni E, Lamberti P, Vanacore N, Meco G, Oostra BA (2005) Early-onset parkinsonism associated with PINK1 mutations: frequency, genotypes, and phenotypes. Neurology 65(1):87–95. doi:10.1212/01.wnl.0000167546.39375.82

    CAS  PubMed  Google Scholar 

  245. Becker D, Richter J, Tocilescu MA, Przedborski S, Voos W (2012) Pink1 kinase and its membrane potential (Deltapsi)-dependent cleavage product both localize to outer mitochondrial membrane by unique targeting mode. J Biol Chem 287(27):22969–22987. doi:10.1074/jbc.M112.365700

    CAS  PubMed Central  PubMed  Google Scholar 

  246. Zhou C, Huang Y, Shao Y, May J, Prou D, Perier C, Dauer W, Schon EA, Przedborski S (2008) The kinase domain of mitochondrial PINK1 faces the cytoplasm. Proc Natl Acad Sci USA 105(33):12022–12027. doi:10.1073/pnas.0802814105

    CAS  PubMed Central  PubMed  Google Scholar 

  247. Matsuda N, Sato S, Shiba K, Okatsu K, Saisho K, Gautier CA, Sou YS, Saiki S, Kawajiri S, Sato F, Kimura M, Komatsu M, Hattori N, Tanaka K (2010) PINK1 stabilized by mitochondrial depolarization recruits Parkin to damaged mitochondria and activates latent Parkin for mitophagy. J Cell Biol 189(2):211–221. doi:10.1083/jcb.200910140

    CAS  PubMed Central  PubMed  Google Scholar 

  248. Narendra DP, Jin SM, Tanaka A, Suen DF, Gautier CA, Shen J, Cookson MR, Youle RJ (2010) PINK1 is selectively stabilized on impaired mitochondria to activate Parkin. PLoS Biol 8(1):e1000298. doi:10.1371/journal.pbio.1000298

    PubMed Central  PubMed  Google Scholar 

  249. Taymans JM, Van den Haute C, Baekelandt V (2006) Distribution of PINK1 and LRRK2 in rat and mouse brain. J Neurochem 98(3):951–961. doi:10.1111/j.1471-4159.2006.03919.x

    CAS  PubMed  Google Scholar 

  250. Wood-Kaczmar A, Gandhi S, Yao Z, Abramov AY, Miljan EA, Keen G, Stanyer L, Hargreaves I, Klupsch K, Deas E, Downward J, Mansfield L, Jat P, Taylor J, Heales S, Duchen MR, Latchman D, Tabrizi SJ, Wood NW (2008) PINK1 is necessary for long term survival and mitochondrial function in human dopaminergic neurons. PLoS ONE 3(6):e2455. doi:10.1371/journal.pone.0002455

    PubMed Central  PubMed  Google Scholar 

  251. Seibler P, Graziotto J, Jeong H, Simunovic F, Klein C, Krainc D (2011) Mitochondrial Parkin recruitment is impaired in neurons derived from mutant PINK1 induced pluripotent stem cells. J Neurosci 31(16):5970–5976. doi:10.1523/jneurosci.4441-10.2011

    CAS  PubMed Central  PubMed  Google Scholar 

  252. Grunewald A, Breedveld GJ, Lohmann-Hedrich K, Rohe CF, Konig IR, Hagenah J, Vanacore N, Meco G, Antonini A, Goldwurm S, Lesage S, Durr A, Binkofski F, Siebner H, Munchau A, Brice A, Oostra BA, Klein C, Bonifati V (2007) Biological effects of the PINK1 c.1366C>T mutation: implications in Parkinson disease pathogenesis. Neurogenetics 8(2):103–109. doi:10.1007/s10048-006-0072-y

    PubMed  Google Scholar 

  253. Cooper O, Seo H, Andrabi S, Guardia-Laguarta C, Graziotto J, Sundberg M, McLean JR, Carrillo-Reid L, Xie Z, Osborn T, Hargus G, Deleidi M, Lawson T, Bogetofte H, Perez-Torres E, Clark L, Moskowitz C, Mazzulli J, Chen L, Volpicelli-Daley L, Romero N, Jiang H, Uitti RJ, Huang Z, Opala G, Scarffe LA, Dawson VL, Klein C, Feng J, Ross OA, Trojanowski JQ, Lee VM, Marder K, Surmeier DJ, Wszolek ZK, Przedborski S, Krainc D, Dawson TM, Isacson O (2012) Pharmacological rescue of mitochondrial deficits in iPSC-derived neural cells from patients with familial Parkinson’s disease. Sci Transl Med 4(141):141ra190. doi:10.1126/scitranslmed.3003985

    Google Scholar 

  254. Lee KS, Wu Z, Song Y, Mitra SS, Feroze AH, Cheshier SH, Lu B (2013) Roles of PINK1, mTORC2, and mitochondria in preserving brain tumor-forming stem cells in a noncanonical Notch signaling pathway. Genes Dev 27(24):2642–2647. doi:10.1101/gad.225169.113

    CAS  PubMed Central  PubMed  Google Scholar 

  255. Bolos V, Grego-Bessa J, de la Pompa JL (2007) Notch signaling in development and cancer. Endocr Rev 28(3):339–363. doi:10.1210/er.2006-0046

    CAS  PubMed  Google Scholar 

  256. Androutsellis-Theotokis A, Leker RR, Soldner F, Hoeppner DJ, Ravin R, Poser SW, Rueger MA, Bae SK, Kittappa R, McKay RD (2006) Notch signalling regulates stem cell numbers in vitro and in vivo. Nature 442(7104):823–826. doi:10.1038/nature04940

    CAS  PubMed  Google Scholar 

  257. Santilli G, Lamorte G, Carlessi L, Ferrari D, Rota Nodari L, Binda E, Delia D, Vescovi AL, De Filippis L (2010) Mild hypoxia enhances proliferation and multipotency of human neural stem cells. PLoS ONE 5(1):e8575. doi:10.1371/journal.pone.0008575

    PubMed Central  PubMed  Google Scholar 

  258. Kondoh H, Lleonart ME, Nakashima Y, Yokode M, Tanaka M, Bernard D, Gil J, Beach D (2007) A high glycolytic flux supports the proliferative potential of murine embryonic stem cells. Antioxid Redox Signal 9(3):293–299. doi:10.1089/ars.2007.9.ft-14

    CAS  PubMed  Google Scholar 

  259. Rodrigues CA, Diogo MM, da Silva CL, Cabral JM (2010) Hypoxia enhances proliferation of mouse embryonic stem cell-derived neural stem cells. Biotechnol Bioeng 106(2):260–270. doi:10.1002/bit.22648

    CAS  PubMed  Google Scholar 

  260. Voccoli V, Colombaioni L (2009) Mitochondrial remodeling in differentiating neuroblasts. Brain Res 1252:15–29. doi:10.1016/j.brainres.2008.11.026

    CAS  PubMed  Google Scholar 

  261. Glasl L, Kloos K, Giesert F, Roethig A, Di Benedetto B, Kuhn R, Zhang J, Hafen U, Zerle J, Hofmann A, de Angelis MH, Winklhofer KF, Holter SM, Vogt Weisenhorn DM, Wurst W (2012) Pink1-deficiency in mice impairs gait, olfaction and serotonergic innervation of the olfactory bulb. Exp Neurol 235(1):214–227. doi:10.1016/j.expneurol.2012.01.002

    CAS  PubMed  Google Scholar 

  262. Klein C, Pramstaller PP, Kis B, Page CC, Kann M, Leung J, Woodward H, Castellan CC, Scherer M, Vieregge P, Breakefield XO, Kramer PL, Ozelius LJ (2000) Parkin deletions in a family with adult-onset, tremor-dominant parkinsonism: expanding the phenotype. Ann Neurol 48(1):65–71

    CAS  PubMed  Google Scholar 

  263. Lucking CB, Durr A, Bonifati V, Vaughan J, De Michele G, Gasser T, Harhangi BS, Meco G, Denefle P, Wood NW, Agid Y, Brice A (2000) Association between early-onset Parkinson’s disease and mutations in the parkin gene. N Engl J Med 342(21):1560–1567. doi:10.1056/nejm200005253422103

    CAS  PubMed  Google Scholar 

  264. Maruyama M, Ikeuchi T, Saito M, Ishikawa A, Yuasa T, Tanaka H, Hayashi S, Wakabayashi K, Takahashi H, Tsuji S (2000) Novel mutations, pseudo-dominant inheritance, and possible familial affects in patients with autosomal recessive juvenile parkinsonism. Ann Neurol 48(2):245–250

    CAS  PubMed  Google Scholar 

  265. Kobayashi T, Wang M, Hattori N, Matsumine H, Kondo T, Mizuno Y (2000) Exonic deletion mutations of the Parkin gene among sporadic patients with Parkinson’s disease. Parkinsonism Relat Disord 6(3):129–131

    PubMed  Google Scholar 

  266. Kitada T, Asakawa S, Hattori N, Matsumine H, Yamamura Y, Minoshima S, Yokochi M, Mizuno Y, Shimizu N (1998) Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 392(6676):605–608. doi:10.1038/33416

    CAS  PubMed  Google Scholar 

  267. Djarmati A, Hedrich K, Svetel M, Schafer N, Juric V, Vukosavic S, Hering R, Riess O, Romac S, Klein C, Kostic V (2004) Detection of Parkin (PARK2) and DJ1 (PARK7) mutations in early-onset Parkinson disease: Parkin mutation frequency depends on ethnic origin of patients. Hum Mutat 23(5):525. doi:10.1002/humu.9240

    PubMed  Google Scholar 

  268. Shimura H, Hattori N, Kubo S, Mizuno Y, Asakawa S, Minoshima S, Shimizu N, Iwai K, Chiba T, Tanaka K, Suzuki T (2000) Familial Parkinson disease gene product, parkin, is a ubiquitin-protein ligase. Nat Genet 25(3):302–305. doi:10.1038/77060

    CAS  PubMed  Google Scholar 

  269. Narendra D, Tanaka A, Suen DF, Youle RJ (2008) Parkin is recruited selectively to impaired mitochondria and promotes their autophagy. J Cell Biol 183(5):795–803. doi:10.1083/jcb.200809125

    CAS  PubMed Central  PubMed  Google Scholar 

  270. Palacino JJ, Sagi D, Goldberg MS, Krauss S, Motz C, Wacker M, Klose J, Shen J (2004) Mitochondrial dysfunction and oxidative damage in parkin-deficient mice. J Biol Chem 279(18):18614–18622. doi:10.1074/jbc.M401135200

    CAS  PubMed  Google Scholar 

  271. Greene JC, Whitworth AJ, Kuo I, Andrews LA, Feany MB, Pallanck LJ (2003) Mitochondrial pathology and apoptotic muscle degeneration in Drosophila parkin mutants. Proc Natl Acad Sci USA 100(7):4078–4083. doi:10.1073/pnas.0737556100

    CAS  PubMed Central  PubMed  Google Scholar 

  272. Hillje AL, Worlitzer MM, Palm T, Schwamborn JC (2011) Neural stem cells maintain their stemness through protein kinase C zeta-mediated inhibition of TRIM32. Stem Cells 29(9):1437–1447. doi:10.1002/stem.687

    CAS  PubMed  Google Scholar 

  273. Hillje AL, Pavlou MA, Beckmann E, Worlitzer MM, Bahnassawy L, Lewejohann L, Palm T, Schwamborn JC (2013) TRIM32-dependent transcription in adult neural progenitor cells regulates neuronal differentiation. Cell Death Dis 4:e976. doi:10.1038/cddis.2013.487

    CAS  PubMed Central  PubMed  Google Scholar 

  274. Schwamborn JC, Berezikov E, Knoblich JA (2009) The TRIM-NHL protein TRIM32 activates microRNAs and prevents self-renewal in mouse neural progenitors. Cell 136(5):913–925. doi:10.1016/j.cell.2008.12.024

    CAS  PubMed Central  PubMed  Google Scholar 

  275. Sarraf SA, Raman M, Guarani-Pereira V, Sowa ME, Huttlin EL, Gygi SP, Harper JW (2013) Landscape of the PARKIN-dependent ubiquitylome in response to mitochondrial depolarization. Nature 496(7445):372–376. doi:10.1038/nature12043

    CAS  PubMed Central  PubMed  Google Scholar 

  276. Hwang M, Lee JM, Kim Y, Geum D (2014) Functional role of Parkin against oxidative stress in neural cells. Endocrinol Metab (Seoul) 29(1):62–69. doi:10.3803/EnM.2014.29.1.62

    Google Scholar 

  277. Imaizumi Y, Okada Y, Akamatsu W, Koike M, Kuzumaki N, Hayakawa H, Nihira T, Kobayashi T, Ohyama M, Sato S, Takanashi M, Funayama M, Hirayama A, Soga T, Hishiki T, Suematsu M, Yagi T, Ito D, Kosakai A, Hayashi K, Shouji M, Nakanishi A, Suzuki N, Mizuno Y, Mizushima N, Amagai M, Uchiyama Y, Mochizuki H, Hattori N, Okano H (2012) Mitochondrial dysfunction associated with increased oxidative stress and alpha-synuclein accumulation in PARK2 iPSC-derived neurons and postmortem brain tissue. Mol Brain 5:35. doi:10.1186/1756-6606-5-35

    CAS  PubMed Central  PubMed  Google Scholar 

  278. Jiang H, Ren Y, Yuen EY, Zhong P, Ghaedi M, Hu Z, Azabdaftari G, Nakaso K, Yan Z, Feng J (2012) Parkin controls dopamine utilization in human midbrain dopaminergic neurons derived from induced pluripotent stem cells. Nat Commun 3:668. doi:10.1038/ncomms1669

    PubMed Central  PubMed  Google Scholar 

  279. Cox RT, Spradling AC (2009) Clueless, a conserved Drosophila gene required for mitochondrial subcellular localization, interacts genetically with parkin. Dis Model Mech 2(9–10):490–499. doi:10.1242/dmm.002378

    CAS  PubMed Central  PubMed  Google Scholar 

  280. Chia W, Somers WG, Wang H (2008) Drosophila neuroblast asymmetric divisions: cell cycle regulators, asymmetric protein localization, and tumorigenesis. J Cell Biol 180(2):267–272. doi:10.1083/jcb.200708159

    CAS  PubMed Central  PubMed  Google Scholar 

  281. Goh LH, Zhou X, Lee MC, Lin S, Wang H, Luo Y, Yang X (2013) Clueless regulates aPKC activity and promotes self-renewal cell fate in Drosophila lgl mutant larval brains. Dev Biol 381(2):353–364. doi:10.1016/j.ydbio.2013.06.031

    CAS  PubMed  Google Scholar 

  282. Sha D, Chin LS, Li L (2010) Phosphorylation of parkin by Parkinson disease-linked kinase PINK1 activates parkin E3 ligase function and NF-kappaB signaling. Hum Mol Genet 19(2):352–363. doi:10.1093/hmg/ddp501

    CAS  PubMed Central  PubMed  Google Scholar 

  283. Beilina A, Van Der Brug M, Ahmad R, Kesavapany S, Miller DW, Petsko GA, Cookson MR (2005) Mutations in PTEN-induced putative kinase 1 associated with recessive parkinsonism have differential effects on protein stability. Proc Natl Acad Sci USA 102(16):5703–5708. doi:10.1073/pnas.0500617102

    CAS  PubMed Central  PubMed  Google Scholar 

  284. Silvestri L, Caputo V, Bellacchio E, Atorino L, Dallapiccola B, Valente EM, Casari G (2005) Mitochondrial import and enzymatic activity of PINK1 mutants associated to recessive parkinsonism. Hum Mol Genet 14(22):3477–3492. doi:10.1093/hmg/ddi377

    CAS  PubMed  Google Scholar 

  285. Sim CH, Lio DS, Mok SS, Masters CL, Hill AF, Culvenor JG, Cheng HC (2006) C-terminal truncation and Parkinson’s disease-associated mutations down-regulate the protein serine/threonine kinase activity of PTEN-induced kinase-1. Hum Mol Genet 15(21):3251–3262. doi:10.1093/hmg/ddl398

    CAS  PubMed  Google Scholar 

  286. Bonifati V, Rizzu P, Squitieri F, Krieger E, Vanacore N, van Swieten JC, Brice A, van Duijn CM, Oostra B, Meco G, Heutink P (2003) DJ-1(PARK7), a novel gene for autosomal recessive, early onset parkinsonism. Neurol Sci 24(3):159–160. doi:10.1007/s10072-003-0108-0

    CAS  PubMed  Google Scholar 

  287. van Duijn CM, Dekker MC, Bonifati V, Galjaard RJ, Houwing-Duistermaat JJ, Snijders PJ, Testers L, Breedveld GJ, Horstink M, Sandkuijl LA, van Swieten JC, Oostra BA, Heutink P (2001) Park7, a novel locus for autosomal recessive early-onset parkinsonism, on chromosome 1p36. Am J Hum Genet 69(3):629–634. doi:10.1086/322996

    PubMed Central  PubMed  Google Scholar 

  288. Healy DG, Abou-Sleiman PM, Valente EM, Gilks WP, Bhatia K, Quinn N, Lees AJ, Wood NW (2004) DJ-1 mutations in Parkinson’s disease. J Neurol Neurosurg Psychiatry 75(1):144–145

    CAS  PubMed Central  PubMed  Google Scholar 

  289. Lee SJ, Kim SJ, Kim IK, Ko J, Jeong CS, Kim GH, Park C, Kang SO, Suh PG, Lee HS, Cha SS (2003) Crystal structures of human DJ-1 and Escherichia coli Hsp31, which share an evolutionarily conserved domain. J Biol Chem 278(45):44552–44559. doi:10.1074/jbc.M304517200

    CAS  PubMed  Google Scholar 

  290. Tao X, Tong L (2003) Crystal structure of human DJ-1, a protein associated with early onset Parkinson’s disease. J Biol Chem 278(33):31372–31379. doi:10.1074/jbc.M304221200

    CAS  PubMed  Google Scholar 

  291. Shendelman S, Jonason A, Martinat C, Leete T, Abeliovich A (2004) DJ-1 is a redox-dependent molecular chaperone that inhibits alpha-synuclein aggregate formation. PLoS Biol 2(11):e362. doi:10.1371/journal.pbio.0020362

    PubMed Central  PubMed  Google Scholar 

  292. Choi J, Sullards MC, Olzmann JA, Rees HD, Weintraub ST, Bostwick DE, Gearing M, Levey AI, Chin LS, Li L (2006) Oxidative damage of DJ-1 is linked to sporadic Parkinson and Alzheimer diseases. J Biol Chem 281(16):10816–10824. doi:10.1074/jbc.M509079200

    CAS  PubMed Central  PubMed  Google Scholar 

  293. Yokota T, Sugawara K, Ito K, Takahashi R, Ariga H, Mizusawa H (2003) Down regulation of DJ-1 enhances cell death by oxidative stress, ER stress, and proteasome inhibition. Biochem Biophys Res Commun 312(4):1342–1348

    CAS  PubMed  Google Scholar 

  294. Taira T, Saito Y, Niki T, Iguchi-Ariga SM, Takahashi K, Ariga H (2004) DJ-1 has a role in antioxidative stress to prevent cell death. EMBO Rep 5(2):213–218. doi:10.1038/sj.embor.7400074

    CAS  PubMed Central  PubMed  Google Scholar 

  295. Takahashi K, Taira T, Niki T, Seino C, Iguchi-Ariga SM, Ariga H (2001) DJ-1 positively regulates the androgen receptor by impairing the binding of PIASx alpha to the receptor. J Biol Chem 276(40):37556–37563. doi:10.1074/jbc.M101730200

    CAS  PubMed  Google Scholar 

  296. Kahle PJ, Waak J, Gasser T (2009) DJ-1 and prevention of oxidative stress in Parkinson’s disease and other age-related disorders. Free Radic Biol Med 47(10):1354–1361. doi:10.1016/j.freeradbiomed.2009.08.003

    CAS  PubMed  Google Scholar 

  297. Li S, Sun Y, Zhao X, Pu XP (2012) Expression of the Parkinson’s disease protein DJ-1 during the differentiation of neural stem cells. Brain Res 1468:84–93. doi:10.1016/j.brainres.2012.05.022

    CAS  PubMed  Google Scholar 

  298. Yan H, Pu XP (2010) Expression of the Parkinson’s disease-related protein DJ-1 during neural stem cell proliferation. Biol Pharm Bull 33(1):18–21

    CAS  PubMed  Google Scholar 

  299. Kaneko Y, Shojo H, Burns J, Staples M, Tajiri N, Borlongan CV (2014) DJ-1 ameliorates ischemic cell death in vitro possibly via mitochondrial pathway. Neurobiol Dis 62:56–61. doi:10.1016/j.nbd.2013.09.007

    CAS  PubMed Central  PubMed  Google Scholar 

  300. Martinat C, Shendelman S, Jonason A, Leete T, Beal MF, Yang L, Floss T, Abeliovich A (2004) Sensitivity to oxidative stress in DJ-1-deficient dopamine neurons: an ES- derived cell model of primary Parkinsonism. PLoS Biol 2(11):e327. doi:10.1371/journal.pbio.0020327

    PubMed Central  PubMed  Google Scholar 

  301. Ding Y-X, Wei L-C, Liu Y-H, Duan L, Jiao X-Y, Xia Y, Chen L-W (2012) Midbrain neural stem cells show unique cell survival, neuronal commitment and neurotrophic properties with therapeutic potential for Parkinson’s disease. J Alzheimers Dis Parkinsonism

  302. Bandopadhyay R, Kingsbury AE, Cookson MR, Reid AR, Evans IM, Hope AD, Pittman AM, Lashley T, Canet-Aviles R, Miller DW, McLendon C, Strand C, Leonard AJ, Abou-Sleiman PM, Healy DG, Ariga H, Wood NW, de Silva R, Revesz T, Hardy JA, Lees AJ (2004) The expression of DJ-1 (PARK7) in normal human CNS and idiopathic Parkinson’s disease. Brain 127(Pt 2):420–430. doi:10.1093/brain/awh054

    PubMed  Google Scholar 

  303. Osman AM, van Dartel DA, Zwart E, Blokland M, Pennings JL, Piersma AH (2010) Proteome profiling of mouse embryonic stem cells to define markers for cell differentiation and embryotoxicity. Reprod Toxicol 30(2):322–332. doi:10.1016/j.reprotox.2010.05.084

    CAS  PubMed  Google Scholar 

  304. Suzukawa K, Miura K, Mitsushita J, Resau J, Hirose K, Crystal R, Kamata T (2000) Nerve growth factor-induced neuronal differentiation requires generation of Rac1-regulated reactive oxygen species. J Biol Chem 275(18):13175–13178

    CAS  PubMed  Google Scholar 

  305. Piao YJ, Seo YH, Hong F, Kim JH, Kim YJ, Kang MH, Kim BS, Jo SA, Jo I, Jue DM, Kang I, Ha J, Kim SS (2005) Nox 2 stimulates muscle differentiation via NF-kappaB/iNOS pathway. Free Radic Biol Med 38(8):989–1001. doi:10.1016/j.freeradbiomed.2004.11.011

    CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by the Fonds National de la Recherche Luxembourg (FNR). Jaclyn Nicole Le Grand and Laura Gonzalez-Cano are supported by fellowships from the FNR (AFR, Aides à la Formation-Recherche).

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  1. Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 4362, Esch-sur-Alzette, Luxembourg

    Jaclyn Nicole Le Grand, Laura Gonzalez-Cano, Maria Angeliki Pavlou & Jens C. Schwamborn

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Le Grand, J.N., Gonzalez-Cano, L., Pavlou, M.A. et al. Neural stem cells in Parkinson’s disease: a role for neurogenesis defects in onset and progression. Cell. Mol. Life Sci. 72, 773–797 (2015). https://doi.org/10.1007/s00018-014-1774-1

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