Advertisement

Acta Neuropathologica

, Volume 135, Issue 1, pp 13–32 | Cite as

Parkinson’s disease: experimental models and reality

Review

Abstract

Parkinson’s disease (PD) is a chronic, progressive movement disorder of adults and the second most common neurodegenerative disease after Alzheimer’s disease. Neuropathologic diagnosis of PD requires moderate-to-marked neuronal loss in the ventrolateral substantia nigra pars compacta and α-synuclein (αS) Lewy body pathology. Nigrostriatal dopaminergic neurodegeneration correlates with the Parkinsonian motor features, but involvement of other peripheral and central nervous system regions leads to a wide range of non-motor features. Nigrostriatal dopaminergic neurodegeneration is shared with other parkinsonian disorders, including some genetic forms of parkinsonism, but many of these disorders do not have Lewy bodies. An ideal animal model for PD, therefore, should exhibit age-dependent and progressive dopaminergic neurodegeneration, motor dysfunction, and abnormal αS pathology. Rodent models of PD using genetic or toxin based strategies have been widely used in the past several decades to investigate the pathogenesis and therapeutics of PD, but few recapitulate all the major clinical and pathologic features of PD. It is likely that new strategies or better understanding of fundamental disease processes may facilitate development of better animal models. In this review, we highlight progress in generating rodent models of PD based on impairments of four major cellular functions: mitochondrial oxidative phosphorylation, autophagy-lysosomal metabolism, ubiquitin–proteasome protein degradation, and endoplasmic reticulum stress/unfolded protein response. We attempt to evaluate how impairment of these major cellular systems contribute to PD and how they can be exploited in rodent models. In addition, we review recent cell biological studies suggesting a link between αS aggregation and impairment of nuclear membrane integrity, as observed during cellular models of apoptosis. We also briefly discuss the role of incompetent phagocytic clearance and how this may be a factor to consider in developing new rodent models of PD.

Notes

Acknowledgements

This study was supported by the National Institute of Health (P50-NS072187 and R21-NS099757) and the Mangurian Foundation Lewy Body Dementia Program at Mayo Clinic (Dickson, Jiang). Neither author has actual or potential conflicts of interest.

References

  1. 1.
    Aharon-Peretz J, Rosenbaum H, Gershoni-Baruch R (2004) Mutations in the glucocerebrosidase gene and Parkinson’s disease in Ashkenazi Jews. New Engl J Med 351:1972–1977.  https://doi.org/10.1056/Nejmoa033277 PubMedCrossRefGoogle Scholar
  2. 2.
    Ahmed I, Liang Y, Schools S, Dawson VL, Dawson TM, Savitt JM (2012) Development and characterization of a new Parkinson’s disease model resulting from impaired autophagy. J Neurosci 32:16503–16509.  https://doi.org/10.1523/JNEUROSCI.0209-12.2012 PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Alafuzoff I, Ince PG, Arzberger T, Al-Sarraj S, Bell J, Bodi I, Bogdanovic N, Bugiani O, Ferrer I, Gelpi E, Gentleman S, Giaccone G, Ironside JW, Kavantzas N, King A, Korkolopoulou P, Kovacs GG, Meyronet D, Monoranu C, Parchi P, Parkkinen L, Patsouris E, Roggendorf W, Rozemuller A, Stadelmann-Nessler C, Streichenberger N, Thal DR, Kretzschmar H (2009) Staging/typing of Lewy body related alpha-synuclein pathology: a study of the BrainNet Europe Consortium. Acta Neuropathol 117:635–652.  https://doi.org/10.1007/s00401-009-0523-2 PubMedCrossRefGoogle Scholar
  4. 4.
    Andres-Mateos E, Perier C, Zhang L, Blanchard-Fillion B, Greco TM, Thomas B, Ko HS, Sasaki M, Ischiropoulos H, Przedborski S, Dawson TM, Dawson VL (2007) DJ-1 gene deletion reveals that DJ-1 is an atypical peroxiredoxin-like peroxidase. Proc Natl Acad Sci USA 104:14807–14812.  https://doi.org/10.1073/pnas.0703219104 PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Anglade P, Vyas S, JavoyAgid F, Herrero MT, Michel PP, Marquez J, MouattPrigent A, Ruberg M, Hirsch EC, Agid Y (1997) Apoptosis and autophagy in nigral neurons of patients with Parkinson’s disease. Histol Histopathol 12:25–31PubMedGoogle Scholar
  6. 6.
    Ariga H, Takahashi-Niki K, Kato I, Maita H, Niki T, Iguchi-Ariga SM (2013) Neuroprotective function of DJ-1 in Parkinson’s disease. Oxid Med Cell Longev 2013:683920.  https://doi.org/10.1155/2013/683920 PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Baiguera C, Alghisi M, Pinna A, Bellucci A, De Luca MA, Frau L, Morelli M, Ingrassia R, Benarese M, Porrini V, Pellitteri M, Bertini G, Fabene PF, Sigala S, Spillantini MG, Liou HC, Spano PF, Pizzi M (2012) Late-onset Parkinsonism in NFkappaB/c-Rel-deficient mice. Brain 135:2750–2765.  https://doi.org/10.1093/brain/aws193 PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Barrientos A, Moraes CT (1999) Titrating the effects of mitochondrial complex I impairment in the cell physiology. J Biol Chem 274:16188–16197.  https://doi.org/10.1074/jbc.274.23.16188 PubMedCrossRefGoogle Scholar
  9. 9.
    Beach TG, Adler CH, Lue L, Sue LI, Bachalakuri J, Henry-Watson J, Sasse J, Boyer S, Shirohi S, Brooks R, Eschbacher J, White CL 3rd, Akiyama H, Caviness J, Shill HA, Connor DJ, Sabbagh MN, Walker DG (2009) Unified staging system for Lewy body disorders: correlation with nigrostriatal degeneration, cognitive impairment and motor dysfunction. Acta Neuropathol 117:613–634.  https://doi.org/10.1007/s00401-009-0538-8 PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Beach TG, Adler CH, Serrano G, Sue LI, Walker DG, Dugger BN, Shill HA, Driver-Dunckley E, Caviness JN, Intorcia A, Filon J, Scott S, Garcia A, Hoffman B, Belden CM, Davis KJ, Sabbagh MN (2016) Prevalence of submandibular gland synucleinopathy in Parkinson’s disease, dementia with Lewy bodies and other Lewy body disorders. J Parkinsons Dis 6:153–163.  https://doi.org/10.3233/JPD-150680 PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Beach TG, Adler CH, Sue LI, Vedders L, Lue L, White Iii CL, Akiyama H, Caviness JN, Shill HA, Sabbagh MN, Walker DG (2010) Multi-organ distribution of phosphorylated alpha-synuclein histopathology in subjects with Lewy body disorders. Acta Neuropathol 119:689–702.  https://doi.org/10.1007/s00401-010-0664-3 PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Bedford L, Hay D, Devoy A, Paine S, Powe DG, Seth R, Gray T, Topham I, Fone K, Rezvani N, Mee M, Soane T, Layfield R, Sheppard PW, Ebendal T, Usoskin D, Lowe J, Mayer RJ (2008) Depletion of 26S proteasomes in mouse brain neurons causes neurodegeneration and Lewy-like inclusions resembling human pale bodies. J Neurosci 28:8189–8198.  https://doi.org/10.1523/JNEUROSCI.2218-08.2008 PubMedCrossRefGoogle Scholar
  13. 13.
    Beecham GW, Dickson DW, Scott WK, Martin ER, Schellenberg G, Nuytemans K, Larson EB, Buxbaum JD, Trojanowski JQ, Van Deerlin VM, Hurtig HI, Mash DC, Beach TG, Troncoso JC, Pletnikova O, Frosch MP, Ghetti B, Foroud TM, Honig LS, Marder K, Vonsattel JP, Goldman SM, Vinters HV, Ross OA, Wszolek ZK, Wang L, Dykxhoorn DM, Pericak-Vance MA, Montine TJ, Leverenz JB, Dawson TM, Vance JM (2015) PARK10 is a major locus for sporadic neuropathologically confirmed Parkinson disease. Neurology 84:972–980.  https://doi.org/10.1212/WNL.0000000000001332 PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Belal C, Ameli NJ, El Kommos A, Bezalel S, Al’Khafaji AM, Mughal MR, Mattson MP, Kyriazis GA, Tyrberg B, Chan SL (2012) The homocysteine-inducible endoplasmic reticulum (ER) stress protein Herp counteracts mutant alpha-synuclein-induced ER stress via the homeostatic regulation of ER-resident calcium release channel proteins. Hum Mol Genet 21:963–977.  https://doi.org/10.1093/hmg/ddr502 PubMedCrossRefGoogle Scholar
  15. 15.
    Bennett MC, Bishop JF, Leng Y, Chock PB, Chase TN, Mouradian MM (1999) Degradation of alpha-synuclein by proteasome. J Biol Chem 274:33855–33858PubMedCrossRefGoogle Scholar
  16. 16.
    Bentea E, Van der Perren A, Van Liefferinge J, El Arfani A, Albertini G, Demuyser T, Merckx E, Michotte Y, Smolders I, Baekelandt V, Massie A (2015) Nigral proteasome inhibition in mice leads to motor and non-motor deficits and increased expression of Ser129 phosphorylated alpha-synuclein. Front Behav Neurosci 9:68.  https://doi.org/10.3389/fnbeh.2015.00068 PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Bhattacharjee N, Borah A (2016) Oxidative stress and mitochondrial dysfunction are the underlying events of dopaminergic neurodegeneration in homocysteine rat model of Parkinson’s disease. Neurochem Int 101:48–55.  https://doi.org/10.1016/j.neuint.2016.10.001 PubMedCrossRefGoogle Scholar
  18. 18.
    Blandini F, Armentero MT, Martignoni E (2008) The 6-hydroxydopamine model: news from the past. Parkinsonism Relat Disord 14(Suppl 2):S124–S129.  https://doi.org/10.1016/j.parkreldis.2008.04.015 PubMedCrossRefGoogle Scholar
  19. 19.
    Bonifati V, Rizzu P, van Baren MJ, Schaap O, Breedveld GJ, Krieger E, Dekker MC, Squitieri F, Ibanez P, Joosse M, van Dongen JW, Vanacore N, van Swieten JC, Brice A, Meco G, van Duijn CM, Oostra BA, Heutink P (2003) Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism. Science 299:256–259.  https://doi.org/10.1126/science.1077209 PubMedCrossRefGoogle Scholar
  20. 20.
    Bove J, Zhou C, Jackson-Lewis V, Taylor J, Chu Y, Rideout HJ, Wu DC, Kordower JH, Petrucelli L, Przedborski S (2006) Proteasome inhibition and Parkinson’s disease modeling. Ann Neurol 60:260–264.  https://doi.org/10.1002/ana.20937 PubMedCrossRefGoogle Scholar
  21. 21.
    Braak H, Bohl JR, Muller CM, Rub U, de Vos RA, Del Tredici K (2006) Stanley Fahn Lecture 2005: the staging procedure for the inclusion body pathology associated with sporadic Parkinson’s disease reconsidered. Mov Disord 21:2042–2051.  https://doi.org/10.1002/mds.21065 PubMedCrossRefGoogle Scholar
  22. 22.
    Braak H, Del Tredici K (2017) Neuropathological staging of brain pathology in sporadic Parkinson’s disease: separating the wheat from the chaff. J Parkinsons Dis 7:S73–S87.  https://doi.org/10.3233/JPD-179001 PubMedPubMedCentralGoogle Scholar
  23. 23.
    Braak H, Del Tredici K, Rub U, de Vos RA, Jansen Steur EN, Braak E (2003) Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging 24:197–211PubMedCrossRefGoogle Scholar
  24. 24.
    Brooks AI, Chadwick CA, Gelbard HA, Cory-Slechta DA, Federoff HJ (1999) Paraquat elicited neurobehavioral syndrome caused by dopaminergic neuron loss. Brain Res 823:1–10PubMedCrossRefGoogle Scholar
  25. 25.
    Bukhatwa S, Zeng BY, Rose S, Jenner P (2010) A comparison of changes in proteasomal subunit expression in the substantia nigra in Parkinson’s disease, multiple system atrophy and progressive supranuclear palsy. Brain Res 1326:174–183.  https://doi.org/10.1016/j.brainres.2010.02.045 PubMedCrossRefGoogle Scholar
  26. 26.
    Casadei N, Sood P, Ulrich T, Fallier-Becker P, Kieper N, Helling S, May C, Glaab E, Chen J, Nuber S, Wolburg H, Marcus K, Rapaport D, Ott T, Riess O, Kruger R, Fitzgerald JC (2016) Mitochondrial defects and neurodegeneration in mice overexpressing wild-type or G399S mutant HtrA2. Hum Mol Genet.  https://doi.org/10.1093/hmg/ddw353 Google Scholar
  27. 27.
    Casey DE (1997) The relationship of pharmacology to side effects. J Clin Psychiatry 58:55–62PubMedGoogle Scholar
  28. 28.
    Chan NC, Salazar AM, Pham AH, Sweredoski MJ, Kolawa NJ, Graham RL, Hess S, Chan DC (2011) Broad activation of the ubiquitin-proteasome system by Parkin is critical for mitophagy. Hum Mol Genet 20:1726–1737.  https://doi.org/10.1093/hmg/ddr048 PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Chandran JS, Lin X, Zapata A, Hoke A, Shimoji M, Moore SO, Galloway MP, Laird FM, Wong PC, Price DL, Bailey KR, Crawley JN, Shippenberg T, Cai H (2008) Progressive behavioral deficits in DJ-1-deficient mice are associated with normal nigrostriatal function. Neurobiol Dis 29:505–514.  https://doi.org/10.1016/j.nbd.2007.11.011 PubMedCrossRefGoogle Scholar
  30. 30.
    Chen L, Cagniard B, Mathews T, Jones S, Koh HC, Ding Y, Carvey PM, Ling Z, Kang UJ, Zhuang X (2005) Age-dependent motor deficits and dopaminergic dysfunction in DJ-1 null mice. J Biol Chem 280:21418–21426.  https://doi.org/10.1074/jbc.M413955200 PubMedCrossRefGoogle Scholar
  31. 31.
    Chen Q, Vazquez EJ, Moghaddas S, Hoppel CL, Lesnefsky EJ (2003) Production of reactive oxygen species by mitochondria: central role of complex III. J Biol Chem 278:36027–36031.  https://doi.org/10.1074/jbc.M304854200 PubMedCrossRefGoogle Scholar
  32. 32.
    Chesselet MF, Richter F, Zhu C, Magen I, Watson MB, Subramaniam SR (2012) A progressive mouse model of Parkinson’s disease: the Thy1-aSyn (“Line 61”) mice. Neurotherapeutics 9:297–314.  https://doi.org/10.1007/s13311-012-0104-2 PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Chu VT, Weber T, Graf R, Sommermann T, Petsch K, Sack U, Volchkov P, Rajewsky K, Kuhn R (2016) Efficient generation of Rosa26 knock-in mice using CRISPR/Cas9 in C57BL/6 zygotes. BMC Biotechnol 16:4.  https://doi.org/10.1186/s12896-016-0234-4 PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Cicchetti F, Drouin-Ouellet J, Gross RE (2009) Environmental toxins and Parkinson’s disease: what have we learned from pesticide-induced animal models? Trends Pharmacol Sci 30:475–483.  https://doi.org/10.1016/j.tips.2009.06.005 PubMedCrossRefGoogle Scholar
  35. 35.
    Conn KJ, Gao W, McKee A, Lan MS, Ullman MD, Eisenhauer PB, Fine RE, Wells JM (2004) Identification of the protein disulfide isomerase family member PDIp in experimental Parkinson’s disease and Lewy body pathology. Brain Res 1022:164–172.  https://doi.org/10.1016/j.brainres.2004.07.026 PubMedCrossRefGoogle Scholar
  36. 36.
    Coppola-Segovia V, Cavarsan C, Maia FG, Ferraz AC, Nakao LS, Lima MM, Zanata SM (2016) ER stress induced by tunicamycin triggers alpha-synuclein oligomerization, dopaminergic neurons death and locomotor impairment: a new model of Parkinson’s disease. Mol Neurobiol.  https://doi.org/10.1007/s12035-016-0114-x PubMedGoogle Scholar
  37. 37.
    Cullen V, Lindfors M, Ng J, Paetau A, Swinton E, Kolodziej P, Boston H, Saftig P, Woulfe J, Feany MB, Myllykangas L, Schlossmacher MG, Tyynela J (2009) Cathepsin D expression level affects alpha-synuclein processing, aggregation, and toxicity in vivo. Mol Brain 2:5.  https://doi.org/10.1186/1756-6606-2-5 PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Daher JP, Ying M, Banerjee R, McDonald RS, Hahn MD, Yang L, Flint Beal M, Thomas B, Dawson VL, Dawson TM, Moore DJ (2009) Conditional transgenic mice expressing C-terminally truncated human alpha-synuclein (alphaSyn119) exhibit reduced striatal dopamine without loss of nigrostriatal pathway dopaminergic neurons. Mol Neurodegener 4:34.  https://doi.org/10.1186/1750-1326-4-34 PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Dave KD, De Silva S, Sheth NP, Ramboz S, Beck MJ, Quang C, Switzer RC 3rd, Ahmad SO, Sunkin SM, Walker D, Cui X, Fisher DA, McCoy AM, Gamber K, Ding X, Goldberg MS, Benkovic SA, Haupt M, Baptista MA, Fiske BK, Sherer TB, Frasier MA (2014) Phenotypic characterization of recessive gene knockout rat models of Parkinson’s disease. Neurobiol Dis 70:190–203.  https://doi.org/10.1016/j.nbd.2014.06.009 PubMedCrossRefGoogle Scholar
  40. 40.
    Dawson TM, Dawson VL (2003) Rare genetic mutations shed light on the pathogenesis of Parkinson disease. J Clin Investig 111:145–151.  https://doi.org/10.1172/JCI17575 PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Dawson TM, Dawson VL (2010) The role of parkin in familial and sporadic Parkinson’s disease. Mov Disord 25(Suppl 1):S32–S39.  https://doi.org/10.1002/mds.22798 PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Decressac M, Mattsson B, Lundblad M, Weikop P, Bjorklund A (2012) Progressive neurodegenerative and behavioural changes induced by AAV-mediated overexpression of alpha-synuclein in midbrain dopamine neurons. Neurobiol Dis 45:939–953.  https://doi.org/10.1016/j.nbd.2011.12.013 PubMedCrossRefGoogle Scholar
  43. 43.
    Dehay B, Bove J, Rodriguez-Muela N, Perier C, Recasens A, Boya P, Vila M (2010) Pathogenic lysosomal depletion in Parkinson’s disease. J Neurosci 30:12535–12544.  https://doi.org/10.1523/Jneurosci.1920-10.2010 PubMedCrossRefGoogle Scholar
  44. 44.
    Dehay B, Martinez-Vicente M, Caldwell GA, Caldwell KA, Yue Z, Cookson MR, Klein C, Vila M, Bezard E (2013) Lysosomal impairment in Parkinson’s disease. Mov Disord 28:725–732.  https://doi.org/10.1002/mds.25462 PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Dickson DW (2017) Neuropathology of Parkinson disease. Parkinsonism Relat Disord.  https://doi.org/10.1016/j.parkreldis.2017.07.033 Google Scholar
  46. 46.
    Domico LM, Zeevalk GD, Bernard LP, Cooper KR (2006) Acute neurotoxic effects of mancozeb and maneb in mesencephalic neuronal cultures are associated with mitochondrial dysfunction. Neurotoxicology 27:816–825.  https://doi.org/10.1016/j.neuro.2006.07.009 PubMedCrossRefGoogle Scholar
  47. 47.
    Duan W, Ladenheim B, Cutler RG, Kruman II, Cadet JL, Mattson MP (2002) Dietary folate deficiency and elevated homocysteine levels endanger dopaminergic neurons in models of Parkinson’s disease. J Neurochem 80:101–110PubMedCrossRefGoogle Scholar
  48. 48.
    Ejlerskov P, Hultberg JG, Wang J, Carlsson R, Ambjorn M, Kuss M, Liu Y, Porcu G, Kolkova K, Friis Rundsten C, Ruscher K, Pakkenberg B, Goldmann T, Loreth D, Prinz M, Rubinsztein DC, Issazadeh-Navikas S (2015) Lack of neuronal IFN-beta-IFNAR causes Lewy body- and Parkinson’s disease-like dementia. Cell 163:324–339.  https://doi.org/10.1016/j.cell.2015.08.069 PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Ekstrand MI, Terzioglu M, Galter D, Zhu S, Hofstetter C, Lindqvist E, Thams S, Bergstrand A, Hansson FS, Trifunovic A, Hoffer B, Cullheim S, Mohammed AH, Olson L, Larsson NG (2007) Progressive parkinsonism in mice with respiratory-chain-deficient dopamine neurons. Proc Natl Acad Sci USA 104:1325–1330.  https://doi.org/10.1073/pnas.0605208103 PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Emmer KL, Waxman EA, Covy JP, Giasson BI (2011) E46K human alpha-synuclein transgenic mice develop Lewy-like and tau pathology associated with age-dependent, detrimental motor impairment. J Biol Chem 286:35104–35118.  https://doi.org/10.1074/jbc.M111.247965 PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Enquist IB, Lo Bianco C, Ooka A, Nilsson E, Mansson JE, Ehinger M, Richter J, Brady RO, Kirik D, Karlsson S (2007) Murine models of acute neuronopathic Gaucher disease. Proc Natl Acad Sci USA 104:17483–17488.  https://doi.org/10.1073/pnas.0708086104 PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Escobar VD, Kuo YM, Orrison BM, Giasson BI, Nussbaum RL (2014) Transgenic mice expressing S129 phosphorylation mutations in alpha-synuclein. Neurosci Lett 563:96–100.  https://doi.org/10.1016/j.neulet.2014.01.033 PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Farrer M, Kachergus J, Forno L, Lincoln S, Wang DS, Hulihan M, Maraganore D, Gwinn-Hardy K, Wszolek Z, Dickson D, Langston JW (2004) Comparison of kindreds with parkinsonism and alpha-synuclein genomic multiplications. Ann Neurol 55:174–179.  https://doi.org/10.1002/ana.10846 PubMedCrossRefGoogle Scholar
  54. 54.
    Fernagut PO, Hutson CB, Fleming SM, Tetreaut NA, Salcedo J, Masliah E, Chesselet MF (2007) Behavioral and histopathological consequences of paraquat intoxication in mice: effects of alpha-synuclein over-expression. Synapse 61:991–1001.  https://doi.org/10.1002/syn.20456 PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Ferrari CC, Tarelli R (2011) Parkinson’s disease and systemic inflammation. Parkinsons Dis 2011:436813.  https://doi.org/10.4061/2011/436813 PubMedPubMedCentralGoogle Scholar
  56. 56.
    Fifel K, Cooper HM (2014) Loss of dopamine disrupts circadian rhythms in a mouse model of Parkinson’s disease. Neurobiol Dis 71:359–369.  https://doi.org/10.1016/j.nbd.2014.08.024 PubMedCrossRefGoogle Scholar
  57. 57.
    Fitsanakis VA, Amarnath V, Moore JT, Montine KS, Zhang J, Montine TJ (2002) Catalysis of catechol oxidation by metal-dithiocarbamate complexes in pesticides. Free Radic Biol Med 33:1714–1723PubMedCrossRefGoogle Scholar
  58. 58.
    Fornai F, Schluter OM, Lenzi P, Gesi M, Ruffoli R, Ferrucci M, Lazzeri G, Busceti CL, Pontarelli F, Battaglia G, Pellegrini A, Nicoletti F, Ruggieri S, Paparelli A, Sudhof TC (2005) Parkinson-like syndrome induced by continuous MPTP infusion: convergent roles of the ubiquitin-proteasome system and alpha-synuclein. Proc Natl Acad Sci USA 102:3413–3418.  https://doi.org/10.1073/pnas.0409713102 PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Forno LS, DeLanney LE, Irwin I, Langston JW (1993) Similarities and differences between MPTP-induced parkinsonsim and Parkinson’s disease. Neuropathologic considerations. Adv Neurol 60:600–608PubMedGoogle Scholar
  60. 60.
    Franco-Iborra S, Vila M, Perier C (2016) The Parkinson disease mitochondrial hypothesis: where are we at? Neuroscientist 22:266–277.  https://doi.org/10.1177/1073858415574600 PubMedCrossRefGoogle Scholar
  61. 61.
    Gash DM, Rutland K, Hudson NL, Sullivan PG, Bing G, Cass WA, Pandya JD, Liu M, Choi DY, Hunter RL, Gerhardt GA, Smith CD, Slevin JT, Prince TS (2008) Trichloroethylene: Parkinsonism and complex 1 mitochondrial neurotoxicity. Ann Neurol 63:184–192.  https://doi.org/10.1002/ana.21288 PubMedCrossRefGoogle Scholar
  62. 62.
    Giasson BI, Duda JE, Quinn SM, Zhang B, Trojanowski JQ, Lee VM (2002) Neuronal alpha-synucleinopathy with severe movement disorder in mice expressing A53T human alpha-synuclein. Neuron 34:521–533PubMedCrossRefGoogle Scholar
  63. 63.
    Gispert S, Del Turco D, Garrett L, Chen A, Bernard DJ, Hamm-Clement J, Korf HW, Deller T, Braak H, Auburger G, Nussbaum RL (2003) Transgenic mice expressing mutant A53T human alpha-synuclein show neuronal dysfunction in the absence of aggregate formation. Mol Cell Neurosci 24:419–429PubMedCrossRefGoogle Scholar
  64. 64.
    Gispert S, Ricciardi F, Kurz A, Azizov M, Hoepken HH, Becker D, Voos W, Leuner K, Muller WE, Kudin AP, Kunz WS, Zimmermann A, Roeper J, Wenzel D, Jendrach M, Garcia-Arencibia M, Fernandez-Ruiz J, Huber L, Rohrer H, Barrera M, Reichert AS, Rub U, Chen A, Nussbaum RL, Auburger G (2009) Parkinson phenotype in aged PINK1-deficient mice is accompanied by progressive mitochondrial dysfunction in absence of neurodegeneration. PLoS One 4:e5777.  https://doi.org/10.1371/journal.pone.0005777 PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    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 235:214–227.  https://doi.org/10.1016/j.expneurol.2012.01.002 PubMedCrossRefGoogle Scholar
  66. 66.
    Goldberg MS, Fleming SM, Palacino JJ, Cepeda C, Lam HA, Bhatnagar A, Meloni EG, Wu N, Ackerson LC, Klapstein GJ, Gajendiran M, Roth BL, Chesselet MF, Maidment NT, Levine MS, Shen J (2003) Parkin-deficient mice exhibit nigrostriatal deficits but not loss of dopaminergic neurons. J Biol Chem 278:43628–43635.  https://doi.org/10.1074/jbc.M308947200 PubMedCrossRefGoogle Scholar
  67. 67.
    Goldberg MS, Pisani A, Haburcak M, Vortherms TA, Kitada T, Costa C, Tong Y, Martella G, Tscherter A, Martins A, Bernardi G, Roth BL, Pothos EN, Calabresi P, Shen J (2005) Nigrostriatal dopaminergic deficits and hypokinesia caused by inactivation of the familial Parkinsonism-linked gene DJ-1. Neuron 45:489–496.  https://doi.org/10.1016/j.neuron.2005.01.041 PubMedCrossRefGoogle Scholar
  68. 68.
    Goldman SM (2014) Environmental toxins and Parkinson’s disease. Annu Rev Pharmacol Toxicol 54:141–164.  https://doi.org/10.1146/annurev-pharmtox-011613-135937 PubMedCrossRefGoogle Scholar
  69. 69.
    Goldman SM, Quinlan PJ, Ross GW, Marras C, Meng C, Bhudhikanok GS, Comyns K, Korell M, Chade AR, Kasten M, Priestley B, Chou KL, Fernandez HH, Cambi F, Langston JW, Tanner CM (2012) Solvent exposures and Parkinson disease risk in twins. Ann Neurol 71:776–784.  https://doi.org/10.1002/ana.22629 PubMedCrossRefGoogle Scholar
  70. 70.
    Gomez-Isla T, Irizarry MC, Mariash A, Cheung B, Soto O, Schrump S, Sondel J, Kotilinek L, Day J, Schwarzschild MA, Cha JH, Newell K, Miller DW, Ueda K, Young AB, Hyman BT, Ashe KH (2003) Motor dysfunction and gliosis with preserved dopaminergic markers in human alpha-synuclein A30P transgenic mice. Neurobiol Aging 24:245–258PubMedCrossRefGoogle Scholar
  71. 71.
    Gomez-Suaga P, Fdez E, Blanca Ramirez M, Hilfiker S (2012) A link between autophagy and the pathophysiology of LRRK2 in Parkinson’s disease. Parkinsons Dis 2012:324521.  https://doi.org/10.1155/2012/324521 PubMedPubMedCentralGoogle Scholar
  72. 72.
    Gonzalez-Reyes LE, Verbitsky M, Blesa J, Jackson-Lewis V, Paredes D, Tillack K, Phani S, Kramer ER, Przedborski S, Kottmann AH (2012) Sonic hedgehog maintains cellular and neurochemical homeostasis in the adult nigrostriatal circuit. Neuron 75:306–319.  https://doi.org/10.1016/j.neuron.2012.05.018 PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Good CH, Hoffman AF, Hoffer BJ, Chefer VI, Shippenberg TS, Backman CM, Larsson NG, Olson L, Gellhaar S, Galter D, Lupica CR (2011) Impaired nigrostriatal function precedes behavioral deficits in a genetic mitochondrial model of Parkinson’s disease. Faseb J 25:1333–1344.  https://doi.org/10.1096/fj.10-173625 PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Grozdanov V, Bliederhaeuser C, Ruf WP, Roth V, Fundel-Clemens K, Zondler L, Brenner D, Martin-Villalba A, Hengerer B, Kassubek J, Ludolph AC, Weishaupt JH, Danzer KM (2014) Inflammatory dysregulation of blood monocytes in Parkinson’s disease patients. Acta Neuropathol 128:651–663.  https://doi.org/10.1007/s00401-014-1345-4 PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Gu G, Reyes PE, Golden GT, Woltjer RL, Hulette C, Montine TJ, Zhang J (2002) Mitochondrial DNA deletions/rearrangements in parkinson disease and related neurodegenerative disorders. J Neuropathol Exp Neurol 61:634–639PubMedCrossRefGoogle Scholar
  76. 76.
    Guehl D, Bezard E, Dovero S, Boraud T, Bioulac B, Gross C (1999) Trichloroethylene and parkinsonism: a human and experimental observation. Eur J Neurol 6:609–611PubMedCrossRefGoogle Scholar
  77. 77.
    Gully JC, Sergeyev VG, Bhootada Y, Mendez-Gomez H, Meyers CA, Zolotukhin S, Gorbatyuk MS, Gorbatyuk OS (2016) Up-regulation of activating transcription factor 4 induces severe loss of dopamine nigral neurons in a rat model of Parkinson’s disease. Neurosci Lett 627:36–41.  https://doi.org/10.1016/j.neulet.2016.05.039 PubMedCrossRefGoogle Scholar
  78. 78.
    Hall K, Yang S, Sauchanka O, Spillantini MG, Anichtchik O (2015) Behavioural deficits in transgenic mice expressing human truncated (1–120 amino acid) alpha-synuclein. Exp Neurol 264:8–13.  https://doi.org/10.1016/j.expneurol.2014.11.003 PubMedCrossRefGoogle Scholar
  79. 79.
    Hashida K, Kitao Y, Sudo H, Awa Y, Maeda S, Mori K, Takahashi R, Iinuma M, Hori O (2012) ATF6alpha promotes astroglial activation and neuronal survival in a chronic mouse model of Parkinson’s disease. PLoS One 7:e47950.  https://doi.org/10.1371/journal.pone.0047950 PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Hoozemans JJ, van Haastert ES, Eikelenboom P, de Vos RA, Rozemuller JM, Scheper W (2007) Activation of the unfolded protein response in Parkinson’s disease. Biochem Biophys Res Commun 354:707–711.  https://doi.org/10.1016/j.bbrc.2007.01.043 PubMedCrossRefGoogle Scholar
  81. 81.
    Howell N, Elson JL, Chinnery PF, Turnbull DM (2005) mtDNA mutations and common neurodegenerative disorders. Trends Genet 21:583–586.  https://doi.org/10.1016/j.tig.2005.08.012 PubMedCrossRefGoogle Scholar
  82. 82.
    Hwang DY, Ardayfio P, Kang UJ, Semina EV, Kim KS (2003) Selective loss of dopaminergic neurons in the substantia nigra of Pitx3-deficient aphakia mice. Brain Res Mol Brain Res 114:123–131PubMedCrossRefGoogle Scholar
  83. 83.
    Iglesias-Gonzalez J, Sanchez-Iglesias S, Mendez-Alvarez E, Rose S, Hikima A, Jenner P, Soto-Otero R (2012) Differential toxicity of 6-hydroxydopamine in SH-SY5Y human neuroblastoma cells and rat brain mitochondria: protective role of catalase and superoxide dismutase. Neurochem Res 37:2150–2160.  https://doi.org/10.1007/s11064-012-0838-6 PubMedCrossRefGoogle Scholar
  84. 84.
    Ikeda M, Kawarabayashi T, Harigaya Y, Sasaki A, Yamada S, Matsubara E, Murakami T, Tanaka Y, Kurata T, Wuhua X, Ueda K, Kuribara H, Ikarashi Y, Nakazato Y, Okamoto K, Abe K, Shoji M (2009) Motor impairment and aberrant production of neurochemicals in human alpha-synuclein A30P+ A53T transgenic mice with alpha-synuclein pathology. Brain Res 1250:232–241.  https://doi.org/10.1016/j.brainres.2008.10.011 PubMedCrossRefGoogle Scholar
  85. 85.
    Ikemura M, Saito Y, Sengoku R, Sakiyama Y, Hatsuta H, Kanemaru K, Sawabe M, Arai T, Ito G, Iwatsubo T, Fukayama M, Murayama S (2008) Lewy body pathology involves cutaneous nerves. J Neuropathol Exp Neurol 67:945–953.  https://doi.org/10.1097/NEN.0b013e318186de48 PubMedCrossRefGoogle Scholar
  86. 86.
    Janezic S, Threlfell S, Dodson PD, Dowie MJ, Taylor TN, Potgieter D, Parkkinen L, Senior SL, Anwar S, Ryan B, Deltheil T, Kosillo P, Cioroch M, Wagner K, Ansorge O, Bannerman DM, Bolam JP, Magill PJ, Cragg SJ, Wade-Martins R (2013) Deficits in dopaminergic transmission precede neuron loss and dysfunction in a new Parkinson model. Proc Natl Acad Sci USA 110:E4016–E4025.  https://doi.org/10.1073/pnas.1309143110 PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Jellinger K, Linert L, Kienzl E, Herlinger E, Youdim MB (1995) Chemical evidence for 6-hydroxydopamine to be an endogenous toxic factor in the pathogenesis of Parkinson’s disease. J Neural Transm Suppl 46:297–314PubMedGoogle Scholar
  88. 88.
    Jiang P, Gan M, Ebrahim AS, Lin WL, Melrose HL, Yen SH (2010) ER stress response plays an important role in aggregation of alpha-synuclein. Mol Neurodegener 5:56.  https://doi.org/10.1186/1750-1326-5-56 PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Jiang P, Gan M, Lin WL, Yen SH (2014) Nutrient deprivation induces alpha-synuclein aggregation through endoplasmic reticulum stress response and SREBP2 pathway. Front Aging Neurosci 6:268.  https://doi.org/10.3389/fnagi.2014.00268 PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Jiang P, Gan M, Yen SH, Moussaud S, McLean PJ, Dickson DW (2016) Proaggregant nuclear factor(s) trigger rapid formation of alpha-synuclein aggregates in apoptotic neurons. Acta Neuropathol 132:77–91.  https://doi.org/10.1007/s00401-016-1542-4 PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Kadkhodaei B, Ito T, Joodmardi E, Mattsson B, Rouillard C, Carta M, Muramatsu S, Sumi-Ichinose C, Nomura T, Metzger D, Chambon P, Lindqvist E, Larsson NG, Olson L, Bjorklund A, Ichinose H, Perlmann T (2009) Nurr1 is required for maintenance of maturing and adult midbrain dopamine neurons. J Neurosci 29:15923–15932.  https://doi.org/10.1523/JNEUROSCI.3910-09.2009 PubMedCrossRefGoogle Scholar
  92. 92.
    Kalivendi SV, Cunningham S, Kotamraju S, Joseph J, Hillard CJ, Kalyanaraman B (2004) Alpha-synuclein up-regulation and aggregation during MPP+-induced apoptosis in neuroblastoma cells: intermediacy of transferrin receptor iron and hydrogen peroxide. J Biol Chem 279:15240–15247.  https://doi.org/10.1074/jbc.M312497200 PubMedCrossRefGoogle Scholar
  93. 93.
    Keeney PM, Xie J, Capaldi RA, Bennett JP Jr (2006) Parkinson’s disease brain mitochondrial complex I has oxidatively damaged subunits and is functionally impaired and misassembled. J Neurosci 26:5256–5264.  https://doi.org/10.1523/JNEUROSCI.0984-06.2006 PubMedCrossRefGoogle Scholar
  94. 94.
    Kett LR, Stiller B, Bernath MM, Tasset I, Blesa J, Jackson-Lewis V, Chan RB, Zhou B, Di Paolo G, Przedborski S, Cuervo AM, Dauer WT (2015) alpha-Synuclein-independent histopathological and motor deficits in mice lacking the endolysosomal Parkinsonism protein Atp13a2. J Neurosci 35:5724–5742.  https://doi.org/10.1523/JNEUROSCI.0632-14.2015 PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Kim HW, Choi WS, Sorscher N, Park HJ, Tronche F, Palmiter RD, Xia Z (2015) Genetic reduction of mitochondrial complex I function does not lead to loss of dopamine neurons in vivo. Neurobiol Aging 36:2617–2627.  https://doi.org/10.1016/j.neurobiolaging.2015.05.008 PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Kim RH, Smith PD, Aleyasin H, Hayley S, Mount MP, Pownall S, Wakeham A, You-Ten AJ, Kalia SK, Horne P, Westaway D, Lozano AM, Anisman H, Park DS, Mak TW (2005) Hypersensitivity of DJ-1-deficient mice to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine (MPTP) and oxidative stress. Proc Natl Acad Sci USA 102:5215–5220.  https://doi.org/10.1073/pnas.0501282102 PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Kirik D, Rosenblad C, Burger C, Lundberg C, Johansen TE, Muzyczka N, Mandel RJ, Bjorklund A (2002) Parkinson-like neurodegeneration induced by targeted overexpression of alpha-synuclein in the nigrostriatal system. J Neurosci 22:2780–2791PubMedGoogle Scholar
  98. 98.
    Klein C, Westenberger A (2012) Genetics of Parkinson’s disease. Cold Spring Harb Perspect Med 2:a008888.  https://doi.org/10.1101/cshperspect.a008888 PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Krige D, Carroll MT, Cooper JM, Marsden CD, Schapira AH (1992) Platelet mitochondrial function in Parkinson’s disease. The Royal Kings and Queens Parkinson Disease Research Group. Ann Neurol 32:782–788.  https://doi.org/10.1002/ana.410320612 PubMedCrossRefGoogle Scholar
  100. 100.
    Krishnan S, Chi EY, Wood SJ, Kendrick BS, Li C, Garzon-Rodriguez W, Wypych J, Randolph TW, Narhi LO, Biere AL, Citron M, Carpenter JF (2003) Oxidative dimer formation is the critical rate-limiting step for Parkinson’s disease alpha-synuclein fibrillogenesis. Biochemistry 42:829–837.  https://doi.org/10.1021/bi026528t PubMedCrossRefGoogle Scholar
  101. 101.
    Kuhn W, Roebroek R, Blom H, van Oppenraaij D, Przuntek H, Kretschmer A, Buttner T, Woitalla D, Muller T (1998) Elevated plasma levels of homocysteine in Parkinson’s disease. Eur Neurol 40:225–227PubMedCrossRefGoogle Scholar
  102. 102.
    Kupsch A, Schmidt W, Gizatullina Z, Debska-Vielhaber G, Voges J, Striggow F, Panther P, Schwegler H, Heinze HJ, Vielhaber S, Gellerich FN (2014) 6-Hydroxydopamine impairs mitochondrial function in the rat model of Parkinson’s disease: respirometric, histological, and behavioral analyses. J Neural Transm (Vienna) 121:1245–1257.  https://doi.org/10.1007/s00702-014-1185-3 CrossRefGoogle Scholar
  103. 103.
    Langston JW (2006) The Parkinson’s complex: parkinsonism is just the tip of the iceberg. Ann Neurol 59:591–596.  https://doi.org/10.1002/ana.20834 PubMedCrossRefGoogle Scholar
  104. 104.
    Langston JW, Langston EB, Irwin I (1984) MPTP-induced parkinsonism in human and non-human primates–clinical and experimental aspects. Acta Neurol Scand Suppl 100:49–54PubMedGoogle Scholar
  105. 105.
    Lauwers E, Beque D, Van Laere K, Nuyts J, Bormans G, Mortelmans L, Casteels C, Vercammen L, Bockstael O, Nuttin B, Debyser Z, Baekelandt V (2007) Non-invasive imaging of neuropathology in a rat model of alpha-synuclein overexpression. Neurobiol Aging 28:248–257.  https://doi.org/10.1016/j.neurobiolaging.2005.12.005 PubMedCrossRefGoogle Scholar
  106. 106.
    Lee MK, Stirling W, Xu Y, Xu X, Qui D, Mandir AS, Dawson TM, Copeland NG, Jenkins NA, Price DL (2002) Human alpha-synuclein-harboring familial Parkinson’s disease-linked Ala-53 →Thr mutation causes neurodegenerative disease with alpha-synuclein aggregation in transgenic mice. Proc Natl Acad Sci USA 99:8968–8973.  https://doi.org/10.1073/pnas.132197599 PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    Leroy E, Boyer R, Auburger G, Leube B, Ulm G, Mezey E, Harta G, Brownstein MJ, Jonnalagada S, Chernova T, Dehejia A, Lavedan C, Gasser T, Steinbach PJ, Wilkinson KD, Polymeropoulos MH (1998) The ubiquitin pathway in Parkinson’s disease. Nature 395:451–452.  https://doi.org/10.1038/26652 PubMedCrossRefGoogle Scholar
  108. 108.
    Li Y, Liu W, Oo TF, Wang L, Tang Y, Jackson-Lewis V, Zhou C, Geghman K, Bogdanov M, Przedborski S, Beal MF, Burke RE, Li C (2009) Mutant LRRK2(R1441G) BAC transgenic mice recapitulate cardinal features of Parkinson’s disease. Nat Neurosci 12:826–828.  https://doi.org/10.1038/nn.2349 PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Lill CM, Roehr JT, McQueen MB, Kavvoura FK, Bagade S, Schjeide BM, Schjeide LM, Meissner E, Zauft U, Allen NC, Liu T, Schilling M, Anderson KJ, Beecham G, Berg D, Biernacka JM, Brice A, DeStefano AL, Do CB, Eriksson N, Factor SA, Farrer MJ, Foroud T, Gasser T, Hamza T, Hardy JA, Heutink P, Hill-Burns EM, Klein C, Latourelle JC, Maraganore DM, Martin ER, Martinez M, Myers RH, Nalls MA, Pankratz N, Payami H, Satake W, Scott WK, Sharma M, Singleton AB, Stefansson K, Toda T, Tung JY, Vance J, Wood NW, Zabetian CP, Young P, Tanzi RE, Khoury MJ, Zipp F, Lehrach H, Ioannidis JP, Bertram L (2012) Comprehensive research synopsis and systematic meta-analyses in Parkinson’s disease genetics: the PDGene database. PLoS Genet 8:e1002548.  https://doi.org/10.1371/journal.pgen.1002548 PubMedPubMedCentralCrossRefGoogle Scholar
  110. 110.
    Lim KL (2007) Ubiquitin-proteasome system dysfunction in Parkinson’s disease: current evidence and controversies. Expert Rev Proteom 4:769–781.  https://doi.org/10.1586/14789450.4.6.769 CrossRefGoogle Scholar
  111. 111.
    Lin X, Parisiadou L, Sgobio C, Liu G, Yu J, Sun L, Shim H, Gu XL, Luo J, Long CX, Ding J, Mateo Y, Sullivan PH, Wu LG, Goldstein DS, Lovinger D, Cai H (2012) Conditional expression of Parkinson’s disease-related mutant alpha-synuclein in the midbrain dopaminergic neurons causes progressive neurodegeneration and degradation of transcription factor nuclear receptor related 1. J Neurosci 32:9248–9264.  https://doi.org/10.1523/JNEUROSCI.1731-12.2012 PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Liu M, Choi DY, Hunter RL, Pandya JD, Cass WA, Sullivan PG, Kim HC, Gash DM, Bing G (2010) Trichloroethylene induces dopaminergic neurodegeneration in Fisher 344 rats. J Neurochem 112:773–783.  https://doi.org/10.1111/j.1471-4159.2009.06497.x PubMedCrossRefGoogle Scholar
  113. 113.
    Lorenc-Koci E, Lenda T, Antkiewicz-Michaluk L, Wardas J, Domin H, Smialowska M, Konieczny J (2011) Different effects of intranigral and intrastriatal administration of the proteasome inhibitor lactacystin on typical neurochemical and histological markers of Parkinson’s disease in rats. Neurochem Int 58:839–849.  https://doi.org/10.1016/j.neuint.2011.03.013 PubMedCrossRefGoogle Scholar
  114. 114.
    Lu XH, Fleming SM, Meurers B, Ackerson LC, Mortazavi F, Lo V, Hernandez D, Sulzer D, Jackson GR, Maidment NT, Chesselet MF, Yang XW (2009) Bacterial artificial chromosome transgenic mice expressing a truncated mutant parkin exhibit age-dependent hypokinetic motor deficits, dopaminergic neuron degeneration, and accumulation of proteinase K-resistant alpha-synuclein. J Neurosci 29:1962–1976.  https://doi.org/10.1523/JNEUROSCI.5351-08.2009 PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Luk KC, Kehm VM, Zhang B, O’Brien P, Trojanowski JQ, Lee VM (2012) Intracerebral inoculation of pathological alpha-synuclein initiates a rapidly progressive neurodegenerative alpha-synucleinopathy in mice. J Exp Med 209:975–986.  https://doi.org/10.1084/jem.20112457 PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Luk KC, Lee VM (2014) Modeling Lewy pathology propagation in Parkinson’s disease. Parkinsonism Relat Disord 20(Suppl 1):S85–S87.  https://doi.org/10.1016/S1353-8020(13)70022-1 PubMedPubMedCentralCrossRefGoogle Scholar
  117. 117.
    Lynch-Day MA, Mao K, Wang K, Zhao M, Klionsky DJ (2012) The role of autophagy in Parkinson’s disease. Cold Spring Harb Perspect Med 2:a009357.  https://doi.org/10.1101/cshperspect.a009357 PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    Magnoni R, Palmfeldt J, Christensen JH, Sand M, Maltecca F, Corydon TJ, West M, Casari G, Bross P (2013) Late onset motoneuron disorder caused by mitochondrial Hsp60 chaperone deficiency in mice. Neurobiol Dis 54:12–23.  https://doi.org/10.1016/j.nbd.2013.02.012 PubMedCrossRefGoogle Scholar
  119. 119.
    Manning-Bog AB, Caudle WM, Perez XA, Reaney SH, Paletzki R, Isla MZ, Chou VP, McCormack AL, Miller GW, Langston JW, Gerfen CR, Dimonte DA (2007) Increased vulnerability of nigrostriatal terminals in DJ-1-deficient mice is mediated by the dopamine transporter. Neurobiol Dis 27:141–150.  https://doi.org/10.1016/j.nbd.2007.03.014 PubMedCrossRefGoogle Scholar
  120. 120.
    Manning-Bog AB, McCormack AL, Li J, Uversky VN, Fink AL, Di Monte DA (2002) The herbicide paraquat causes up-regulation and aggregation of alpha-synuclein in mice: paraquat and alpha-synuclein. J Biol Chem 277:1641–1644.  https://doi.org/10.1074/jbc.C100560200 PubMedCrossRefGoogle Scholar
  121. 121.
    Manzoni C (2012) LRRK2 and autophagy: a common pathway for disease. Biochem Soc Trans 40:1147–1151.  https://doi.org/10.1042/BST20120126 PubMedCrossRefGoogle Scholar
  122. 122.
    Maraganore DM, Lesnick TG, Elbaz A, Chartier-Harlin MC, Gasser T, Kruger R, Hattori N, Mellick GD, Quattrone A, Satoh J, Toda T, Wang J, Ioannidis JP, de Andrade M, Rocca WA (2004) UCHL1 is a Parkinson’s disease susceptibility gene. Ann Neurol 55:512–521.  https://doi.org/10.1002/ana.20017 PubMedCrossRefGoogle Scholar
  123. 123.
    Martella G, Platania P, Vita D, Sciamanna G, Cuomo D, Tassone A, Tscherter A, Kitada T, Bonsi P, Shen J, Pisani A (2009) Enhanced sensitivity to group II mGlu receptor activation at corticostriatal synapses in mice lacking the familial parkinsonism-linked genes PINK1 or Parkin. Exp Neurol 215:388–396.  https://doi.org/10.1016/j.expneurol.2008.11.001 PubMedCrossRefGoogle Scholar
  124. 124.
    Martinez TN, Greenamyre JT (2012) Toxin models of mitochondrial dysfunction in Parkinson’s disease. Antioxid Redox Signal 16:920–934.  https://doi.org/10.1089/ars.2011.4033 PubMedPubMedCentralCrossRefGoogle Scholar
  125. 125.
    Masliah E, Rockenstein E, Veinbergs I, Mallory M, Hashimoto M, Takeda A, Sagara Y, Sisk A, Mucke L (2000) Dopaminergic loss and inclusion body formation in alpha-synuclein mice: implications for neurodegenerative disorders. Science 287:1265–1269PubMedCrossRefGoogle Scholar
  126. 126.
    Matsuoka Y, Vila M, Lincoln S, McCormack A, Picciano M, LaFrancois J, Yu X, Dickson D, Langston WJ, McGowan E, Farrer M, Hardy J, Duff K, Przedborski S, Di Monte DA (2001) Lack of nigral pathology in transgenic mice expressing human alpha-synuclein driven by the tyrosine hydroxylase promoter. Neurobiol Dis 8:535–539.  https://doi.org/10.1006/nbdi.2001.0392 PubMedCrossRefGoogle Scholar
  127. 127.
    McCormack AL, Thiruchelvam M, Manning-Bog AB, Thiffault C, Langston JW, Cory-Slechta DA, Di Monte DA (2002) Environmental risk factors and Parkinson’s disease: selective degeneration of nigral dopaminergic neurons caused by the herbicide paraquat. Neurobiol Dis 10:119–127PubMedCrossRefGoogle Scholar
  128. 128.
    McDowell K, Chesselet MF (2012) Animal models of the non-motor features of Parkinson’s disease. Neurobiol Dis 46:597–606.  https://doi.org/10.1016/j.nbd.2011.12.040 PubMedPubMedCentralCrossRefGoogle Scholar
  129. 129.
    McNaught KS, Belizaire R, Jenner P, Olanow CW, Isacson O (2002) Selective loss of 20S proteasome alpha-subunits in the substantia nigra pars compacta in Parkinson’s disease. Neurosci Lett 326:155–158PubMedCrossRefGoogle Scholar
  130. 130.
    McNaught KS, Jackson T, JnoBaptiste R, Kapustin A, Olanow CW (2006) Proteasomal dysfunction in sporadic Parkinson’s disease. Neurology 66:S37–S49PubMedCrossRefGoogle Scholar
  131. 131.
    McNaught KS, Olanow CW, Halliwell B, Isacson O, Jenner P (2001) Failure of the ubiquitin-proteasome system in Parkinson’s disease. Nat Rev Neurosci 2:589–594.  https://doi.org/10.1038/35086067 PubMedCrossRefGoogle Scholar
  132. 132.
    McNaught KS, Perl DP, Brownell AL, Olanow CW (2004) Systemic exposure to proteasome inhibitors causes a progressive model of Parkinson’s disease. Ann Neurol 56:149–162.  https://doi.org/10.1002/ana.20186 PubMedCrossRefGoogle Scholar
  133. 133.
    Mercado G, Valdes P, Hetz C (2013) An ERcentric view of Parkinson’s disease. Trends Mol Med 19:165–175.  https://doi.org/10.1016/j.molmed.2012.12.005 PubMedCrossRefGoogle Scholar
  134. 134.
    Meredith GE, Rademacher DJ (2011) MPTP mouse models of Parkinson’s disease: an update. J Parkinsons Dis 1:19–33.  https://doi.org/10.3233/JPD-2011-11023 PubMedPubMedCentralGoogle Scholar
  135. 135.
    Miller GW (2007) Paraquat: the red herring of Parkinson’s disease research. Toxicol Sci 100:1–2.  https://doi.org/10.1093/toxsci/kfm223 PubMedCrossRefGoogle Scholar
  136. 136.
    Mizuno Y, Ohta S, Tanaka M, Takamiya S, Suzuki K, Sato T, Oya H, Ozawa T, Kagawa Y (1989) Deficiencies in complex I subunits of the respiratory chain in Parkinson’s disease. Biochem Biophys Res Commun 163:1450–1455PubMedCrossRefGoogle Scholar
  137. 137.
    Moisoi N, Fedele V, Edwards J, Martins LM (2014) Loss of PINK1 enhances neurodegeneration in a mouse model of Parkinson’s disease triggered by mitochondrial stress. Neuropharmacology 77:350–357.  https://doi.org/10.1016/j.neuropharm.2013.10.009 PubMedPubMedCentralCrossRefGoogle Scholar
  138. 138.
    Moon HE, Paek SH (2015) Mitochondrial dysfunction in Parkinson’s disease. Exp Neurobiol 24:103–116.  https://doi.org/10.5607/en.2015.24.2.103 PubMedPubMedCentralCrossRefGoogle Scholar
  139. 139.
    Moscovitz O, Ben-Nissan G, Fainer I, Pollack D, Mizrachi L, Sharon M (2015) The Parkinson’s-associated protein DJ-1 regulates the 20S proteasome. Nat Commun 6:6609.  https://doi.org/10.1038/ncomms7609 PubMedCrossRefGoogle Scholar
  140. 140.
    Nalls MA, Pankratz N, Lill CM, Do CB, Hernandez DG, Saad M, DeStefano AL, Kara E, Bras J, Sharma M, Schulte C, Keller MF, Arepalli S, Letson C, Edsall C, Stefansson H, Liu X, Pliner H, Lee JH, Cheng R, Ikram MA, Ioannidis JP, Hadjigeorgiou GM, Bis JC, Martinez M, Perlmutter JS, Goate A, Marder K, Fiske B, Sutherland M, Xiromerisiou G, Myers RH, Clark LN, Stefansson K, Hardy JA, Heutink P, Chen H, Wood NW, Houlden H, Payami H, Brice A, Scott WK, Gasser T, Bertram L, Eriksson N, Foroud T, Singleton AB (2014) Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson’s disease. Nat Genet 46:989–993.  https://doi.org/10.1038/ng.3043 PubMedPubMedCentralCrossRefGoogle Scholar
  141. 141.
    Narendra D, Tanaka A, Suen DF, Youle RJ (2008) Parkin is recruited selectively to impaired mitochondria and promotes their autophagy. J Cell Biol 183:795–803.  https://doi.org/10.1083/jcb.200809125 PubMedPubMedCentralCrossRefGoogle Scholar
  142. 142.
    Nordstrom U, Beauvais G, Ghosh A, Pulikkaparambil Sasidharan BC, Lundblad M, Fuchs J, Joshi RL, Lipton JW, Roholt A, Medicetty S, Feinstein TN, Steiner JA, Escobar Galvis ML, Prochiantz A, Brundin P (2015) Progressive nigrostriatal terminal dysfunction and degeneration in the engrailed1 heterozygous mouse model of Parkinson’s disease. Neurobiol Dis 73:70–82.  https://doi.org/10.1016/j.nbd.2014.09.012 CrossRefGoogle Scholar
  143. 143.
    Nussbaum RL, Ellis CE (2003) Alzheimer’s disease and Parkinson’s disease. New Engl J Med 348:1356–1364.  https://doi.org/10.1056/NEJM2003ra020003 PubMedCrossRefGoogle Scholar
  144. 144.
    Obeso JA, Stamelou M, Goetz CG, Poewe W, Lang AE, Weintraub D, Burn D, Halliday GM, Bezard E, Przedborski S, Lehericy S, Brooks DJ, Rothwell JC, Hallett M, DeLong MR, Marras C, Tanner CM, Ross GW, Langston JW, Klein C, Bonifati V, Jankovic J, Lozano AM, Deuschl G, Bergman H, Tolosa E, Rodriguez-Violante M, Fahn S, Postuma RB, Berg D, Marek K, Standaert DG, Surmeier DJ, Olanow CW, Kordower JH, Calabresi P, Schapira AHV, Stoessl AJ (2017) Past, present, and future of Parkinson’s disease: a special essay on the 200th anniversary of the Shaking Palsy. Mov Disord 32:1264–1310.  https://doi.org/10.1002/mds.27115 PubMedCrossRefGoogle Scholar
  145. 145.
    Osellame LD, Rahim AA, Hargreaves IP, Gegg ME, Richard-Londt A, Brandner S, Waddington SN, Schapira AH, Duchen MR (2013) Mitochondria and quality control defects in a mouse model of Gaucher disease–links to Parkinson’s disease. Cell Metab 17:941–953.  https://doi.org/10.1016/j.cmet.2013.04.014 PubMedPubMedCentralCrossRefGoogle Scholar
  146. 146.
    Paine SM, Anderson G, Bedford K, Lawler K, Mayer RJ, Lowe J, Bedford L (2013) Pale body-like inclusion formation and neurodegeneration following depletion of 26S proteasomes in mouse brain neurones are independent of alpha-synuclein. PLoS One 8:e54711.  https://doi.org/10.1371/journal.pone.0054711 PubMedPubMedCentralCrossRefGoogle Scholar
  147. 147.
    Palmeira CM, Moreno AJ, Madeira VMC (1995) Mitochondrial bioenergetics is affected by the herbicide paraquat. Bba Bioenergetics 1229:187–192.  https://doi.org/10.1016/0005-2728(94)00202-G PubMedCrossRefGoogle Scholar
  148. 148.
    Palomo-Garo C, Gomez-Galvez Y, Garcia C, Fernandez-Ruiz J (2016) Targeting the cannabinoid CB2 receptor to attenuate the progression of motor deficits in LRRK2-transgenic mice. Pharmacol Res 110:181–192.  https://doi.org/10.1016/j.phrs.2016.04.004 PubMedCrossRefGoogle Scholar
  149. 149.
    Pan TH, Kondo S, Le WD, Jankovic J (2008) The role of autophagy-lysosome pathway in neurodegeneration associated with Parkinson’s disease. Brain 131:1969–1978.  https://doi.org/10.1093/brain/awm318 PubMedCrossRefGoogle Scholar
  150. 150.
    Park JS, Blair NF, Sue CM (2015) The role of ATP13A2 in Parkinson’s disease: clinical phenotypes and molecular mechanisms. Mov Disord 30:770–779.  https://doi.org/10.1002/mds.26243 PubMedCrossRefGoogle Scholar
  151. 151.
    Parker WD Jr, Boyson SJ, Parks JK (1989) Abnormalities of the electron transport chain in idiopathic Parkinson’s disease. Ann Neurol 26:719–723.  https://doi.org/10.1002/ana.410260606 PubMedCrossRefGoogle Scholar
  152. 152.
    Patterson VL, Zullo AJ, Koenig C, Stoessel S, Jo H, Liu X, Han J, Choi M, DeWan AT, Thomas JL, Kuan CY, Hoh J (2014) Neural-specific deletion of Htra2 causes cerebellar neurodegeneration and defective processing of mitochondrial OPA1. PLoS One 9:e115789.  https://doi.org/10.1371/journal.pone.0115789 PubMedPubMedCentralCrossRefGoogle Scholar
  153. 153.
    Perez FA, Palmiter RD (2005) Parkin-deficient mice are not a robust model of parkinsonism. Proc Natl Acad Sci USA 102:2174–2179.  https://doi.org/10.1073/pnas.0409598102 PubMedPubMedCentralCrossRefGoogle Scholar
  154. 154.
    Perier C, Vila M (2012) Mitochondrial biology and Parkinson’s disease. Cold Spring Harb Perspect Med 2:a009332.  https://doi.org/10.1101/cshperspect.a009332 PubMedPubMedCentralCrossRefGoogle Scholar
  155. 155.
    Pfeiffer RF (2016) Non-motor symptoms in Parkinson’s disease. Parkinsonism Relat Disord 22(Suppl 1):S119–S122.  https://doi.org/10.1016/j.parkreldis.2015.09.004 PubMedCrossRefGoogle Scholar
  156. 156.
    Pickrell AM, Pinto M, Hida A, Moraes CT (2011) Striatal dysfunctions associated with mitochondrial DNA damage in dopaminergic neurons in a mouse model of Parkinson’s disease. J Neurosci 31:17649–17658.  https://doi.org/10.1523/JNEUROSCI.4871-11.2011 PubMedPubMedCentralCrossRefGoogle Scholar
  157. 157.
    Pollanen MS, Dickson DW, Bergeron C (1993) Pathology and biology of the Lewy body. J Neuropathol Exp Neurol 52:183–191PubMedCrossRefGoogle Scholar
  158. 158.
    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 276:2045–2047PubMedCrossRefGoogle Scholar
  159. 159.
    Poulopoulos M, Levy OA, Alcalay RN (2012) The neuropathology of genetic Parkinson’s disease. Mov Disord 27:831–842.  https://doi.org/10.1002/mds.24962 PubMedPubMedCentralCrossRefGoogle Scholar
  160. 160.
    Przedborski S, Levivier M, Jiang H, Ferreira M, Jackson-Lewis V, Donaldson D, Togasaki DM (1995) Dose-dependent lesions of the dopaminergic nigrostriatal pathway induced by intrastriatal injection of 6-hydroxydopamine. Neuroscience 67:631–647PubMedCrossRefGoogle Scholar
  161. 161.
    Puschmann A, Fiesel FC, Caulfield TR, Hudec R, Ando M, Truban D, Hou X, Ogaki K, Heckman MG, James ED, Swanberg M, Jimenez-Ferrer I, Hansson O, Opala G, Siuda J, Boczarska-Jedynak M, Friedman A, Koziorowski D, Aasly JO, Lynch T, Mellick GD, Mohan M, Silburn PA, Sanotsky Y, Vilarino-Guell C, Farrer MJ, Chen L, Dawson VL, Dawson TM, Wszolek ZK, Ross OA, Springer W (2017) Heterozygous PINK1 p. G411S increases risk of Parkinson’s disease via a dominant-negative mechanism. Brain 140:98–117.  https://doi.org/10.1093/brain/aww261 PubMedCrossRefGoogle Scholar
  162. 162.
    Qiao L, Hamamichi S, Caldwell KA, Caldwell GA, Yacoubian TA, Wilson S, Xie ZL, Speake LD, Parks R, Crabtree D, Liang Q, Crimmins S, Schneider L, Uchiyama Y, Iwatsubo T, Zhou Y, Peng L, Lu Y, Standaert DG, Walls KC, Shacka JJ, Roth KA, Zhang J (2008) Lysosomal enzyme cathepsin D protects against alpha-synuclein aggregation and toxicity. Mol Brain 1:17.  https://doi.org/10.1186/1756-6606-1-17 PubMedPubMedCentralCrossRefGoogle Scholar
  163. 163.
    Ramirez A, Heimbach A, Grundemann J, Stiller B, Hampshire D, Cid LP, Goebel I, Mubaidin AF, Wriekat AL, Roeper J, Al-Din A, Hillmer AM, Karsak M, Liss B, Woods CG, Behrens MI, Kubisch C (2006) Hereditary parkinsonism with dementia is caused by mutations in ATP13A2, encoding a lysosomal type 5 P-type ATPase. Nat Genet 38:1184–1191.  https://doi.org/10.1038/ng1884 PubMedCrossRefGoogle Scholar
  164. 164.
    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:e18568.  https://doi.org/10.1371/journal.pone.0018568 PubMedPubMedCentralCrossRefGoogle Scholar
  165. 165.
    Richardson JR, Quan Y, Sherer TB, Greenamyre JT, Miller GW (2005) Paraquat neurotoxicity is distinct from that of MPTP and rotenone. Toxicol Sci 88:193–201.  https://doi.org/10.1093/toxsci/kfi304 PubMedCrossRefGoogle Scholar
  166. 166.
    Richter G, Sonnenschein A, Grunewald T, Reichmann H, Janetzky B (2002) Novel mitochondrial DNA mutations in Parkinson’s disease. J Neural Transm (Vienna) 109:721–729.  https://doi.org/10.1007/s007020200060 CrossRefGoogle Scholar
  167. 167.
    Rocha EM, Smith GA, Park E, Cao H, Graham AR, Brown E, McLean JR, Hayes MA, Beagan J, Izen SC, Perez-Torres E, Hallett PJ, Isacson O (2015) Sustained systemic glucocerebrosidase inhibition induces brain alpha-synuclein aggregation, microglia and complement C1q activation in mice. Antioxid Redox Signal 23:550–564.  https://doi.org/10.1089/ars.2015.6307 PubMedPubMedCentralCrossRefGoogle Scholar
  168. 168.
    Salganik M, Sergeyev VG, Shinde V, Meyers CA, Gorbatyuk MS, Lin JH, Zolotukhin S, Gorbatyuk OS (2015) The loss of glucose-regulated protein 78 (GRP78) during normal aging or from siRNA knockdown augments human alpha-synuclein (alpha-syn) toxicity to rat nigral neurons. Neurobiol Aging 36:2213–2223.  https://doi.org/10.1016/j.neurobiolaging.2015.02.018 PubMedPubMedCentralCrossRefGoogle Scholar
  169. 169.
    Salman H, Bergman M, Djaldetti R, Bessler H, Djaldetti M (1999) Decreased phagocytic function in patients with Parkinson’s disease. Biomed Pharmacother 53:146–148.  https://doi.org/10.1016/S0753-3322(99)80080-8 PubMedCrossRefGoogle Scholar
  170. 170.
    Sauer H, Oertel WH (1994) Progressive degeneration of nigrostriatal dopamine neurons following intrastriatal terminal lesions with 6-hydroxydopamine: a combined retrograde tracing and immunocytochemical study in the rat. Neuroscience 59:401–415PubMedCrossRefGoogle Scholar
  171. 171.
    Schapira AH (2015) Glucocerebrosidase and Parkinson disease: recent advances. Mol Cell Neurosci 66:37–42.  https://doi.org/10.1016/j.mcn.2015.03.013 PubMedPubMedCentralCrossRefGoogle Scholar
  172. 172.
    Schapira AH, Cleeter MW, Muddle JR, Workman JM, Cooper JM, King RH (2006) Proteasomal inhibition causes loss of nigral tyrosine hydroxylase neurons. Ann Neurol 60:253–255.  https://doi.org/10.1002/ana.20934 PubMedCrossRefGoogle Scholar
  173. 173.
    Schapira AH, Cooper JM, Dexter D, Jenner P, Clark JB, Marsden CD (1989) Mitochondrial complex I deficiency in Parkinson’s disease. Lancet 1:1269PubMedCrossRefGoogle Scholar
  174. 174.
    Schapira AHV, Chaudhuri KR, Jenner P (2017) Non-motor features of Parkinson disease. Nat Rev Neurosci 18:435–450.  https://doi.org/10.1038/nrn.2017.62 PubMedCrossRefGoogle Scholar
  175. 175.
    Selvaraj S, Sun Y, Watt JA, Wang S, Lei S, Birnbaumer L, Singh BB (2012) Neurotoxin-induced ER stress in mouse dopaminergic neurons involves downregulation of TRPC1 and inhibition of AKT/mTOR signaling. J Clin Investig 122:1354–1367.  https://doi.org/10.1172/JCI61332 PubMedPubMedCentralCrossRefGoogle Scholar
  176. 176.
    Setsuie R, Wang YL, Mochizuki H, Osaka H, Hayakawa H, Ichihara N, Li H, Furuta A, Sano Y, Sun YJ, Kwon J, Kabuta T, Yoshimi K, Aoki S, Mizuno Y, Noda M, Wada K (2007) Dopaminergic neuronal loss in transgenic mice expressing the Parkinson’s disease-associated UCH-L1 I93M mutant. Neurochem Int 50:119–129.  https://doi.org/10.1016/j.neuint.2006.07.015 PubMedCrossRefGoogle Scholar
  177. 177.
    Sevlever D, Jiang P, Yen SH (2008) Cathepsin D is the main lysosomal enzyme involved in the degradation of alpha-synuclein and generation of its carboxy-terminally truncated species. Biochemistry 47:9678–9687.  https://doi.org/10.1021/bi800699v PubMedPubMedCentralCrossRefGoogle Scholar
  178. 178.
    Shi CH, Mao CY, Zhang SY, Yang J, Song B, Wu P, Zuo CT, Liu YT, Ji Y, Yang ZH, Wu J, Zhuang ZP, Xu YM (2016) CHCHD2 gene mutations in familial and sporadic Parkinson’s disease. Neurobiol Aging 38:217.  https://doi.org/10.1016/j.neurobiolaging.2015.10.040 (e219–213) PubMedCrossRefGoogle Scholar
  179. 179.
    Shimshek DR, Schweizer T, Schmid P, van der Putten PH (2012) Excess alpha-synuclein worsens disease in mice lacking ubiquitin carboxy-terminal hydrolase L1. Sci Rep 2:262.  https://doi.org/10.1038/srep00262 PubMedPubMedCentralCrossRefGoogle Scholar
  180. 180.
    Sidransky E, Nalls MA, Aasly JO, Aharon-Peretz J, Annesi G, Barbosa ER, Bar-Shira A, Berg D, Bras J, Brice A, Chen CM, Clark LN, Condroyer C, De Marco EV, Durr A, Eblan MJ, Fahn S, Farrer MJ, Fung HC, Gan-Or Z, Gasser T, Gershoni-Baruch R, Giladi N, Griffith A, Gurevich T, Januario C, Kropp P, Lang AE, Lee-Chen GJ, Lesage S, Marder K, Mata IF, Mirelman A, Mitsui J, Mizuta I, Nicoletti G, Oliveira C, Ottman R, Orr-Urtreger A, Pereira LV, Quattrone A, Rogaeva E, Rolfs A, Rosenbaum H, Rozenberg R, Samii A, Samaddar T, Schulte C, Sharma M, Singleton A, Spitz M, Tan EK, Tayebi N, Toda T, Troiano AR, Tsuji S, Wittstock M, Wolfsberg TG, Wu YR, Zabetian CP, Zhao Y, Ziegler SG (2009) Multicenter analysis of glucocerebrosidase mutations in Parkinson’s Disease. New Engl J Med 361:1651–1661.  https://doi.org/10.1056/Nejmoa0901281 PubMedPubMedCentralCrossRefGoogle Scholar
  181. 181.
    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 302:841.  https://doi.org/10.1126/science.1090278 PubMedCrossRefGoogle Scholar
  182. 182.
    Slodzinski H, Moran LB, Michael GJ, Wang B, Novoselov S, Cheetham ME, Pearce RK, Graeber MB (2009) Homocysteine-induced endoplasmic reticulum protein (herp) is up-regulated in parkinsonian substantia nigra and present in the core of Lewy bodies. Clin Neuropathol 28:333–343PubMedGoogle Scholar
  183. 183.
    Smith GA, Isacson O, Dunnett SB (2012) The search for genetic mouse models of prodromal Parkinson’s disease. Exp Neurol 237:267–273.  https://doi.org/10.1016/j.expneurol.2012.06.035 PubMedCrossRefGoogle Scholar
  184. 184.
    Sokolowski JD, Mandell JW (2011) Phagocytic clearance in neurodegeneration. Am J Pathol 178:1416–1428.  https://doi.org/10.1016/j.ajpath.2010.12.051 PubMedPubMedCentralCrossRefGoogle Scholar
  185. 185.
    Song L, Cortopassi G (2015) Mitochondrial complex I defects increase ubiquitin in substantia nigra. Brain Res 1594:82–91.  https://doi.org/10.1016/j.brainres.2014.11.013 PubMedCrossRefGoogle Scholar
  186. 186.
    Song L, Shan Y, Lloyd KC, Cortopassi GA (2012) Mutant twinkle increases dopaminergic neurodegeneration, mtDNA deletions and modulates Parkin expression. Hum Mol Genet 21:5147–5158.  https://doi.org/10.1093/hmg/dds365 PubMedPubMedCentralCrossRefGoogle Scholar
  187. 187.
    Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M (1997) Alpha-synuclein in Lewy bodies. Nature 388:839–840.  https://doi.org/10.1038/42166 PubMedCrossRefGoogle Scholar
  188. 188.
    Strauss KM, Martins LM, Plun-Favreau H, Marx FP, Kautzmann S, Berg D, Gasser T, Wszolek Z, Muller T, Bornemann A, Wolburg H, Downward J, Riess O, Schulz JB, Kruger R (2005) Loss of function mutations in the gene encoding Omi/HtrA2 in Parkinson’s disease. Hum Mol Genet 14:2099–2111.  https://doi.org/10.1093/hmg/ddi215 PubMedCrossRefGoogle Scholar
  189. 189.
    Sun F, Anantharam V, Zhang D, Latchoumycandane C, Kanthasamy A, Kanthasamy AG (2006) Proteasome inhibitor MG-132 induces dopaminergic degeneration in cell culture and animal models. Neurotoxicology 27:807–815.  https://doi.org/10.1016/j.neuro.2006.06.006 PubMedCrossRefGoogle Scholar
  190. 190.
    Szondy Z, Garabuczi E, Joos G, Tsay GJ, Sarang Z (2014) Impaired clearance of apoptotic cells in chronic inflammatory diseases: therapeutic implications. Front Immunol 5:354.  https://doi.org/10.3389/fimmu.2014.00354 PubMedPubMedCentralCrossRefGoogle Scholar
  191. 191.
    Tagliaferro P, Kareva T, Oo TF, Yarygina O, Kholodilov N, Burke RE (2015) An early axonopathy in a hLRRK2(R1441G) transgenic model of Parkinson disease. Neurobiol Dis 82:359–371.  https://doi.org/10.1016/j.nbd.2015.07.009 PubMedPubMedCentralCrossRefGoogle Scholar
  192. 192.
    Taylor TN, Caudle WM, Miller GW (2011) VMAT2-deficient mice display nigral and extranigral pathology and motor and nonmotor symptoms of parkinson’s disease. Parkinsons Dis 2011:124165.  https://doi.org/10.4061/2011/124165 PubMedPubMedCentralGoogle Scholar
  193. 193.
    Thiruchelvam M, Brockel BJ, Richfield EK, Baggs RB, Cory-Slechta DA (2000) Potentiated and preferential effects of combined paraquat and maneb on nigrostriatal dopamine systems: environmental risk factors for Parkinson’s disease? Brain Res 873:225–234PubMedCrossRefGoogle Scholar
  194. 194.
    Thiruchelvam MJ, Powers JM, Cory-Slechta DA, Richfield EK (2004) Risk factors for dopaminergic neuron loss in human alpha-synuclein transgenic mice. Eur J Neurosci 19:845–854PubMedCrossRefGoogle Scholar
  195. 195.
    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 26:3942–3950.  https://doi.org/10.1523/JNEUROSCI.4965-05.2006 PubMedCrossRefGoogle Scholar
  196. 196.
    Toledo JB, Gopal P, Raible K, Irwin DJ, Brettschneider J, Sedor S, Waits K, Boluda S, Grossman M, Van Deerlin VM, Lee EB, Arnold SE, Duda JE, Hurtig H, Lee VM, Adler CH, Beach TG, Trojanowski JQ (2016) Pathological alpha-synuclein distribution in subjects with coincident Alzheimer’s and Lewy body pathology. Acta Neuropathol 131:393–409.  https://doi.org/10.1007/s00401-015-1526-9 PubMedCrossRefGoogle Scholar
  197. 197.
    Ungerstedt U (1968) 6-Hydroxy-dopamine induced degeneration of central monoamine neurons. Eur J Pharmacol 5:107–110PubMedCrossRefGoogle Scholar
  198. 198.
    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 304:1158–1160.  https://doi.org/10.1126/science.1096284 PubMedCrossRefGoogle Scholar
  199. 199.
    Valente EM, Salvi S, Ialongo T, Marongiu R, Elia AE, Caputo V, Romito L, Albanese A, Dallapiccola B, Bentivoglio AR (2004) PINK1 mutations are associated with sporadic early-onset parkinsonism. Ann Neurol 56:336–341.  https://doi.org/10.1002/ana.20256 PubMedCrossRefGoogle Scholar
  200. 200.
    van den Munckhof P, Luk KC, Ste-Marie L, Montgomery J, Blanchet PJ, Sadikot AF, Drouin J (2003) Pitx3 is required for motor activity and for survival of a subset of midbrain dopaminergic neurons. Development 130:2535–2542PubMedCrossRefGoogle Scholar
  201. 201.
    Van Rompuy AS, Lobbestael E, Van der Perren A, Van den Haute C, Baekelandt V (2014) Long-term overexpression of human wild-type and T240R mutant Parkin in rat substantia nigra induces progressive dopaminergic neurodegeneration. J Neuropathol Exp Neurol 73:159–174.  https://doi.org/10.1097/NEN.0000000000000039 PubMedCrossRefGoogle Scholar
  202. 202.
    Varma D, Sen D (2015) Role of the unfolded protein response in the pathogenesis of Parkinson’s disease. Acta Neurobiol Exp (Wars) 75:1–26Google Scholar
  203. 203.
    Vekrellis K, Xilouri M, Emmanouilidou E, Rideout HJ, Stefanis L (2011) Pathological roles of alpha-synuclein in neurological disorders. Lancet Neurol 10:1015–1025.  https://doi.org/10.1016/S1474-4422(11)70213-7 PubMedCrossRefGoogle Scholar
  204. 204.
    Vernon AC, Johansson SM, Modo MM (2010) Non-invasive evaluation of nigrostriatal neuropathology in a proteasome inhibitor rodent model of Parkinson’s disease. BMC Neurosci 11:1.  https://doi.org/10.1186/1471-2202-11-1 PubMedPubMedCentralCrossRefGoogle Scholar
  205. 205.
    Villeneuve LM, Purnell PR, Boska MD, Fox HS (2016) Early Expression of Parkinson’s disease-related mitochondrial abnormalities in PINK1 knockout rats. Mol Neurobiol 53:171–186.  https://doi.org/10.1007/s12035-014-8927-y PubMedCrossRefGoogle Scholar
  206. 206.
    Villeneuve LM, Purnell PR, Stauch KL, Fox HS (2016) Neonatal mitochondrial abnormalities due to PINK1 deficiency: proteomics reveals early changes relevant to Parkinsons disease. Data Brief 6:428–432.  https://doi.org/10.1016/j.dib.2015.11.070 PubMedCrossRefGoogle Scholar
  207. 207.
    Wang X, Yen J, Kaiser P, Huang L (2010) Regulation of the 26S proteasome complex during oxidative stress. Sci Signal 3:ra88.  https://doi.org/10.1126/scisignal.2001232 PubMedPubMedCentralGoogle Scholar
  208. 208.
    Webb JL, Ravikumar B, Atkins J, Skepper JN, Rubinsztein DC (2003) Alpha-synuclein is degraded by both autophagy and the proteasome. J Biol Chem 278:25009–25013.  https://doi.org/10.1074/jbc.M300227200 PubMedCrossRefGoogle Scholar
  209. 209.
    Wey MC, Fernandez E, Martinez PA, Sullivan P, Goldstein DS, Strong R (2012) Neurodegeneration and motor dysfunction in mice lacking cytosolic and mitochondrial aldehyde dehydrogenases: implications for Parkinson’s disease. PLoS One 7:e31522.  https://doi.org/10.1371/journal.pone.0031522 PubMedPubMedCentralCrossRefGoogle Scholar
  210. 210.
    Yasuda T, Nihira T, Ren YR, Cao XQ, Wada K, Setsuie R, Kabuta T, Hattori N, Mizuno Y, Mochizuki H (2009) Effects of UCH-L1 on alpha-synuclein over-expression mouse model of Parkinson’s disease. J Neurochem 108:932–944.  https://doi.org/10.1111/j.1471-4159.2008.05827.x PubMedCrossRefGoogle Scholar
  211. 211.
    Zhang L, Le W, Xie W, Dani JA (2012) Age-related changes in dopamine signaling in Nurr1 deficient mice as a model of Parkinson’s disease. Neurobiol Aging 33(1001):e1007–e1016.  https://doi.org/10.1016/j.neurobiolaging.2011.03.022 Google Scholar
  212. 212.
    Zhu JH, Guo FL, Shelburne J, Watkins S, Chu CT (2003) Localization of phosphorylated ERK/MAP kinases to mitochondria and autophagosomes in Lewy body diseases. Brain Pathol 13:473–481PubMedPubMedCentralCrossRefGoogle Scholar
  213. 213.
    Zhu XR, Maskri L, Herold C, Bader V, Stichel CC, Gunturkun O, Lubbert H (2007) Non-motor behavioural impairments in parkin-deficient mice. Eur J Neurosci 26:1902–1911.  https://doi.org/10.1111/j.1460-9568.2007.05812.x PubMedCrossRefGoogle Scholar
  214. 214.
    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 44:601–607.  https://doi.org/10.1016/j.neuron.2004.11.005 PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2017

Authors and Affiliations

  1. 1.Neuropathology Laboratory, Department of NeuroscienceMayo ClinicJacksonvilleUSA

Personalised recommendations