Cellular and Molecular Life Sciences

, Volume 76, Issue 23, pp 4589–4611 | Cite as

Mechanisms of PINK1, ubiquitin and Parkin interactions in mitochondrial quality control and beyond

  • Andrew N. Bayne
  • Jean-François TrempeEmail author


Parkinson’s disease (PD) is a degenerative movement disorder resulting from the loss of specific neuron types in the midbrain. Early environmental and pathophysiological studies implicated mitochondrial damage and protein aggregation as the main causes of PD. These findings are now vindicated by the characterization of more than 20 genes implicated in rare familial forms of the disease. In particular, two proteins encoded by the Parkin and PINK1 genes, whose mutations cause early-onset autosomal recessive PD, function together in a mitochondrial quality control pathway. In this review, we will describe recent development in our understanding of their mechanisms of action, structure, and function. We explain how PINK1 acts as a mitochondrial damage sensor via the regulated proteolysis of its N-terminus and the phosphorylation of ubiquitin tethered to outer mitochondrial membrane proteins. In turn, phospho-ubiquitin recruits and activates Parkin via conformational changes that increase its ubiquitin ligase activity. We then describe how the formation of polyubiquitin chains on mitochondria triggers the recruitment of the autophagy machinery or the formation of mitochondria-derived vesicles. Finally, we discuss the evidence for the involvement of these mechanisms in physiological processes such as immunity and inflammation, as well as the links to other PD genes.


Parkinson Ubiquitin Kinase Parkin PINK1 Mitochondria 



We would like to thank the members of the Trempe, Gehring, Fon and Durcan labs for stimulating discussions that forged our understanding of the Parkin/PINK1 pathway. A.B. is supported by a Healthy Brain for Healthy LivesCanada First Research Excellence Fund (HBHL-CFREF) (No. 1c-II-5) studentship at McGill University. J.-F.T. is supported by a Tier 2 Canada Research Chair (No. 950-229792) and research grants from the Canadian Institutes of Health Research (No. PJT-153274), Natural Sciences and Engineering Research Council (No. RGPIN-06497), Parkinson Canada (No. 2017-1277), the Michael J. Fox Foundation (No. 14681), and the HBHL-CFREF.

Compliance with ethical standards

Conflict of interest

ANB declares no conflicts of interest. J-FT is a consultant for Mitokinin Inc. and a founding member of M4ND Pharma Inc.


  1. 1.
    Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M (1997) Alpha-synuclein in Lewy bodies. Nature 388:839–840PubMedGoogle Scholar
  2. 2.
    Langston JW, Ballard PA Jr (1983) Parkinson’s disease in a chemist working with 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine. N Engl J Med 309:310PubMedGoogle Scholar
  3. 3.
    Langston JW, Ballard P, Tetrud JW, Irwin I (1983) Chronic Parkinsonism in humans due to a product of meperidine-analog synthesis. Science 219:979–980PubMedGoogle Scholar
  4. 4.
    Schapira AH, Cooper JM, Dexter D, Jenner P, Clark JB, Marsden CD (1989) Mitochondrial complex I deficiency in Parkinson’s disease. Lancet 1:1269PubMedGoogle Scholar
  5. 5.
    Bender A, Krishnan KJ, Morris CM, Taylor GA, Reeve AK, Perry RH, Jaros E, Hersheson JS, Betts J, Klopstock T, Taylor RW, Turnbull DM (2006) High levels of mitochondrial DNA deletions in substantia nigra neurons in aging and Parkinson disease. Nat Genet 38:515–517PubMedGoogle Scholar
  6. 6.
    Martin I, Dawson VL, Dawson TM (2011) Recent advances in the genetics of Parkinson’s disease. Annu Rev Genomics Hum Genet 12:301–325PubMedPubMedCentralGoogle Scholar
  7. 7.
    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 276:2045–2047PubMedGoogle Scholar
  8. 8.
    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 392:605–608PubMedGoogle Scholar
  9. 9.
    Zhang Y, Gao J, Chung KK, Huang H, Dawson VL, Dawson TM (2000) Parkin functions as an E2-dependent ubiquitin- protein ligase and promotes the degradation of the synaptic vesicle-associated protein, CDCrel-1. Proc Natl Acad Sci USA 97:13354–13359PubMedGoogle Scholar
  10. 10.
    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 25:302–305PubMedGoogle Scholar
  11. 11.
    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 304:1158–1160PubMedGoogle Scholar
  12. 12.
    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 44:595–600PubMedGoogle Scholar
  13. 13.
    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 44:601–607PubMedGoogle Scholar
  14. 14.
    Billingsley KJ, Bandres-Ciga S, Saez-Atienzar S, Singleton AB (2018) Genetic risk factors in Parkinson’s disease. Cell Tissue Res 373:9–20PubMedPubMedCentralGoogle Scholar
  15. 15.
    Winklhofer KF (2014) Parkin and mitochondrial quality control: toward assembling the puzzle. Trends Cell Biol 24:332–341PubMedGoogle Scholar
  16. 16.
    Narendra D, Walker JE, Youle R (2012) Mitochondrial quality control mediated by PINK1 and Parkin: links to Parkinsonism. Cold Spring Harb Perspect Biol 4:a011338PubMedPubMedCentralGoogle Scholar
  17. 17.
    Narendra D, Tanaka A, Suen DF, Youle RJ (2008) Parkin is recruited selectively to impaired mitochondria and promotes their autophagy. J Cell Biol 183:795–803PubMedPubMedCentralGoogle Scholar
  18. 18.
    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 278:43628–43635PubMedGoogle Scholar
  19. 19.
    Esposito G, Ana Clara F, Verstreken P (2012) Synaptic vesicle trafficking and Parkinson’s disease. Dev Neurobiol 72:134–144PubMedGoogle Scholar
  20. 20.
    Trempe JF, Chen CX, Grenier K, Camacho EM, Kozlov G, McPherson PS, Gehring K, Fon EA (2009) SH3 domains from a subset of BAR proteins define a Ubl-binding domain and implicate parkin in synaptic ubiquitination. Mol Cell 36:1034–1047PubMedGoogle Scholar
  21. 21.
    Kim KY, Stevens MV, Akter MH, Rusk SE, Huang RJ, Cohen A, Noguchi A, Springer D, Bocharov AV, Eggerman TL, Suen DF, Youle RJ, Amar M, Remaley AT, Sack MN (2011) Parkin is a lipid-responsive regulator of fat uptake in mice and mutant human cells. J Clin Investig 121:3701–3712PubMedGoogle Scholar
  22. 22.
    Manzanillo PS, Ayres JS, Watson RO, Collins AC, Souza G, Rae CS, Schneider DS, Nakamura K, Shiloh MU, Cox JS (2013) The ubiquitin ligase parkin mediates resistance to intracellular pathogens. Nature 501:512–516PubMedPubMedCentralGoogle Scholar
  23. 23.
    Mira MT, Alcais A, Nguyen VT, Moraes MO, Di Flumeri C, Vu HT, Mai CP, Nguyen TH, Nguyen NB, Pham XK, Sarno EN, Alter A, Montpetit A, Moraes ME, Moraes JR, Dore C, Gallant CJ, Lepage P, Verner A, Van De Vosse E, Hudson TJ, Abel L, Schurr E (2004) Susceptibility to leprosy is associated with PARK2 and PACRG. Nature 427:636–640PubMedGoogle Scholar
  24. 24.
    Sliter DA, Martinez J, Hao L, Chen X, Sun N, Fischer TD, Burman JL, Li Y, Zhang Z, Narendra DP, Cai H, Borsche M, Klein C, Youle RJ (2018) Parkin and PINK1 mitigate STING-induced inflammation. Nature 561:258–262PubMedGoogle Scholar
  25. 25.
    Mouton-Liger F, Rosazza T, Sepulveda-Diaz J, Ieang A, Hassoun SM, Claire E, Mangone G, Brice A, Michel PP, Corvol JC, Corti O (2018) Parkin deficiency modulates NLRP3 inflammasome activation by attenuating an A20-dependent negative feedback loop. Glia 66:1736–1751PubMedPubMedCentralGoogle Scholar
  26. 26.
    Matheoud D, Sugiura A, Bellemare-Pelletier A, Laplante A, Rondeau C, Chemali M, Fazel A, Bergeron JJ, Trudeau LE, Burelle Y, Gagnon E, McBride HM, Desjardins M (2016) Parkinson’s disease-related proteins PINK1 and Parkin repress mitochondrial antigen presentation. Cell 166:314–327PubMedGoogle Scholar
  27. 27.
    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 100:4078–4083PubMedGoogle Scholar
  28. 28.
    Park J, Lee SB, Lee S, Kim Y, Song S, Kim S, Bae E, Kim J, Shong M, Kim JM, Chung J (2006) Mitochondrial dysfunction in Drosophila PINK1 mutants is complemented by parkin. Nature 441:1157–1161PubMedGoogle Scholar
  29. 29.
    Clark IE, Dodson MW, Jiang C, Cao JH, Huh JR, Seol JH, Yoo SJ, Hay BA, Guo M (2006) Drosophila pink1 is required for mitochondrial function and interacts genetically with parkin. Nature 441:1162–1166PubMedGoogle Scholar
  30. 30.
    Ziviani E, Tao RN, Whitworth AJ (2010) Drosophila parkin requires PINK1 for mitochondrial translocation and ubiquitinates mitofusin. Proc Natl Acad Sci USA 107:5018–5023PubMedGoogle Scholar
  31. 31.
    Ordureau A, Paulo JA, Zhang W, Ahfeldt T, Zhang J, Cohn EF, Hou Z, Heo JM, Rubin LL, Sidhu SS, Gygi SP, Harper JW (2018) Dynamics of PARKIN-dependent mitochondrial ubiquitylation in induced neurons and model systems revealed by digital snapshot proteomics. Mol Cell 70:211–227PubMedPubMedCentralGoogle Scholar
  32. 32.
    McLelland GL, Soubannier V, Chen CX, McBride HM, Fon EA (2014) Parkin and PINK1 function in a vesicular trafficking pathway regulating mitochondrial quality control. EMBO J 33:282–295PubMedPubMedCentralGoogle Scholar
  33. 33.
    Vögtle FN, Wortelkamp S, Zahedi RP, Becker D, Leidhold C, Gevaert K, Kellermann J, Voos W, Sickmann A, Pfanner N, Meisinger C (2009) Global analysis of the mitochondrial N-proteome identifies a processing peptidase critical for protein stability. Cell 139:428–439PubMedGoogle Scholar
  34. 34.
    Quirós PM, Langer T, López-Otín C (2015) New roles for mitochondrial proteases in health, ageing and disease. Nat Rev Mol Cell Biol 16:345–59PubMedGoogle Scholar
  35. 35.
    Takatori S, Ito G, Iwatsubo T (2008) Cytoplasmic localization and proteasomal degradation of N-terminally cleaved form of PINK1. Neurosci Lett 430:13–17PubMedGoogle Scholar
  36. 36.
    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 14:3477–3492PubMedGoogle Scholar
  37. 37.
    Petit A, Kawarai T, Paitel E, Sanjo N, Maj M, Scheid M, Chen F, Gu Y, Hasegawa H, Salehi-Rad S, Wang L, Rogaeva E, Fraser P, Robinson B, St George-Hyslop P, Tandon A (2005) Wild-type PINK1 prevents basal and induced neuronal apoptosis, a protective effect abrogated by Parkinson disease-related mutations. J Biol Chem 280:34025–34032PubMedGoogle Scholar
  38. 38.
    Okatsu K, Kimura M, Oka T, Tanaka K, Matsuda N (2015) Unconventional PINK1 localization to the outer membrane of depolarized mitochondria drives Parkin recruitment. J Cell Sci 128:964–978PubMedPubMedCentralGoogle Scholar
  39. 39.
    Woodroof HI, Pogson JH, Begley M, Cantley LC, Deak M, Campbell DG, van Aalten DM, Whitworth AJ, Alessi DR, Muqit MM (2011) Discovery of catalytically active orthologues of the Parkinson’s disease kinase PINK1: analysis of substrate specificity and impact of mutations. Open Biol 1:110012PubMedPubMedCentralGoogle Scholar
  40. 40.
    Sekine S, Wang C, Sideris DP, Bunker E, Zhang Z, Youle RJ (2019) Reciprocal roles of Tom7 and OMA1 during mitochondrial import and activation of PINK1. Mol Cell 73:1028–1043PubMedGoogle Scholar
  41. 41.
    Lazarou M, Jin SM, Kane LA, Youle RJ (2012) Role of PINK1 binding to the TOM complex and alternate intracellular membranes in recruitment and activation of the E3 ligase Parkin. Dev Cell 22:320–333PubMedPubMedCentralGoogle Scholar
  42. 42.
    Wiedemann N, Pfanner N (2017) Mitochondrial machineries for protein import and assembly. Annu Rev Biochem 86:685–714PubMedGoogle Scholar
  43. 43.
    Greene AW, Grenier K, Aguileta MA, Muise S, Farazifard R, Haque ME, McBride HM, Park DS, Fon EA (2012) Mitochondrial processing peptidase regulates PINK1 processing, import and Parkin recruitment. EMBO Rep 13:378–385PubMedPubMedCentralGoogle Scholar
  44. 44.
    Deas E, Plun-Favreau H, Gandhi S, Desmond H, Kjaer S, Loh SH, Renton AE, Harvey RJ, Whitworth AJ, Martins LM, Abramov AY, Wood NW (2011) PINK1 cleavage at position A103 by the mitochondrial protease PARL. Hum Mol Genet 20:867–879PubMedGoogle Scholar
  45. 45.
    Jin SM, Lazarou M, Wang C, Kane LA, Narendra DP, Youle RJ (2010) Mitochondrial membrane potential regulates PINK1 import and proteolytic destabilization by PARL. J Cell Biol 191:933–942PubMedPubMedCentralGoogle Scholar
  46. 46.
    Meissner C, Lorenz H, Weihofen A, Selkoe DJ, Lemberg MK (2011) The mitochondrial intramembrane protease PARL cleaves human Pink1 to regulate Pink1 trafficking. J Neurochem 117:856–867PubMedGoogle Scholar
  47. 47.
    Yamano K, Youle RJ (2013) PINK1 is degraded through the N-end rule pathway. Autophagy 9:1758–1769PubMedPubMedCentralGoogle Scholar
  48. 48.
    Liu Y, Guardia-Laguarta C, Yin J, Erdjument-Bromage H, Martin B, James M, Jiang X, Przedborski S (2017) The ubiquitination of PINK1 is restricted to its mature 52-kDa form. Cell Rep 20:30–39PubMedPubMedCentralGoogle Scholar
  49. 49.
    Sekine S, Youle RJ (2018) PINK1 import regulation; a fine system to convey mitochondrial stress to the cytosol. BMC Biol 16:2PubMedPubMedCentralGoogle Scholar
  50. 50.
    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:e1000298PubMedPubMedCentralGoogle Scholar
  51. 51.
    Okatsu K, Uno M, Koyano F, Go E, Kimura M, Oka T, Tanaka K, Matsuda N (2013) A dimeric PINK1-containing complex on depolarized mitochondria stimulates Parkin recruitment. J Biol Chem 288:36372–36384PubMedPubMedCentralGoogle Scholar
  52. 52.
    Bausewein T, Mills DJ, Langer JD, Nitschke B, Nussberger S, Kuhlbrandt W (2017) Cryo-EM structure of the TOM core complex from Neurospora crassa. Cell 170(693–700):e697Google Scholar
  53. 53.
    Hasson SA, Kane LA, Yamano K, Huang CH, Sliter DA, Buehler E, Wang C, Heman-Ackah SM, Hessa T, Guha R, Martin SE, Youle RJ (2013) High-content genome-wide RNAi screens identify regulators of parkin upstream of mitophagy. Nature 504:291–295PubMedPubMedCentralGoogle Scholar
  54. 54.
    Thomas RE, Andrews LA, Burman JL, Lin WY, Pallanck LJ (2014) PINK1-Parkin pathway activity is regulated by degradation of PINK1 in the mitochondrial matrix. PLoS Genet 10:e1004279PubMedPubMedCentralGoogle Scholar
  55. 55.
    Jin SM, Youle RJ (2013) The accumulation of misfolded proteins in the mitochondrial matrix is sensed by PINK1 to induce PARK2/Parkin-mediated mitophagy of polarized mitochondria. Autophagy 9:1750–1757PubMedPubMedCentralGoogle Scholar
  56. 56.
    Xiao B, Goh JY, Xiao L, Xian H, Lim KL, Liou YC (2017) Reactive oxygen species trigger Parkin/PINK1 pathway-dependent mitophagy by inducing mitochondrial recruitment of Parkin. J Biol Chem 292:16697–16708PubMedPubMedCentralGoogle Scholar
  57. 57.
    Pickrell AM, Huang CH, Kennedy SR, Ordureau A, Sideris DP, Hoekstra JG, Harper JW, Youle RJ (2015) Endogenous Parkin preserves dopaminergic substantia nigral neurons following mitochondrial DNA mutagenic stress. Neuron 87:371–381PubMedPubMedCentralGoogle Scholar
  58. 58.
    Cardona F, Sanchez-Mut JV, Dopazo H, Perez-Tur J (2011) Phylogenetic and in silico structural analysis of the Parkinson disease-related kinase PINK1. Hum Mutat 32:369–378PubMedGoogle Scholar
  59. 59.
    Endicott JA, Noble ME, Johnson LN (2012) The structural basis for control of eukaryotic protein kinases. Annu Rev Biochem 81:587–613PubMedGoogle Scholar
  60. 60.
    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 15:3251–3262PubMedGoogle Scholar
  61. 61.
    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 102:5703–5708PubMedGoogle Scholar
  62. 62.
    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 189:211–221PubMedPubMedCentralGoogle Scholar
  63. 63.
    Geisler S, Holmstrom KM, Skujat D, Fiesel FC, Rothfuss OC, Kahle PJ, Springer W (2010) PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1. Nat Cell Biol 12:119–131PubMedGoogle Scholar
  64. 64.
    Koyano F, Okatsu K, Kosako H, Tamura Y, Go E, Kimura M, Kimura Y, Tsuchiya H, Yoshihara H, Hirokawa T, Endo T, Fon EA, Trempe JF, Saeki Y, Tanaka K, Matsuda N (2014) Ubiquitin is phosphorylated by PINK1 to activate parkin. Nature 510:162–166PubMedPubMedCentralGoogle Scholar
  65. 65.
    Kazlauskaite A, Kondapalli C, Gourlay R, Campbell DG, Ritorto MS, Hofmann K, Alessi DR, Knebel A, Trost M, Muqit MM (2014) Parkin is activated by PINK1-dependent phosphorylation of ubiquitin at Ser65. Biochem J 460:127–139PubMedPubMedCentralGoogle Scholar
  66. 66.
    Kane LA, Lazarou M, Fogel AI, Li Y, Yamano K, Sarraf SA, Banerjee S, Youle RJ (2014) PINK1 phosphorylates ubiquitin to activate Parkin E3 ubiquitin ligase activity. J Cell Biol 205:143–153PubMedPubMedCentralGoogle Scholar
  67. 67.
    Shiba-Fukushima K, Imai Y, Yoshida S, Ishihama Y, Kanao T, Sato S, Hattori N (2012) PINK1-mediated phosphorylation of the Parkin ubiquitin-like domain primes mitochondrial translocation of Parkin and regulates mitophagy. Sci Rep 2:1002PubMedPubMedCentralGoogle Scholar
  68. 68.
    Kondapalli C, Kazlauskaite A, Zhang N, Woodroof HI, Campbell DG, Gourlay R, Burchell L, Walden H, Macartney TJ, Deak M, Knebel A, Alessi DR, Muqit MM (2012) PINK1 is activated by mitochondrial membrane potential depolarization and stimulates Parkin E3 ligase activity by phosphorylating Serine 65. Open Biol 2:120080PubMedPubMedCentralGoogle Scholar
  69. 69.
    Okatsu K, Oka T, Iguchi M, Imamura K, Kosako H, Tani N, Kimura M, Go E, Koyano F, Funayama M, Shiba-Fukushima K, Sato S, Shimizu H, Fukunaga Y, Taniguchi H, Komatsu M, Hattori N, Mihara K, Tanaka K, Matsuda N (2012) PINK1 autophosphorylation upon membrane potential dissipation is essential for Parkin recruitment to damaged mitochondria. Nat Commun 3:1016PubMedPubMedCentralGoogle Scholar
  70. 70.
    Rasool S, Soya N, Truong L, Croteau N, Lukacs GL, Trempe JF (2018) PINK1 autophosphorylation is required for ubiquitin recognition. EMBO Rep 19:e44981PubMedPubMedCentralGoogle Scholar
  71. 71.
    Aerts L, Craessaerts K, De Strooper B, Morais VA (2014) PINK1 catalytic activity is regulated by phosphorylation on serines 228 and 402. J Biol Chem 290:2798–2811PubMedPubMedCentralGoogle Scholar
  72. 72.
    Narendra DP, Wang C, Youle RJ, Walker JE (2013) PINK1 rendered temperature sensitive by disease-associated and engineered mutations. Hum Mol Genet 22:2572–2589PubMedPubMedCentralGoogle Scholar
  73. 73.
    Okatsu K, Sato Y, Yamano K, Matsuda N, Negishi L, Takahashi A, Yamagata A, Goto-Ito S, Mishima M, Ito Y, Oka T, Tanaka K, Fukai S (2018) Structural insights into ubiquitin phosphorylation by PINK1. Sci Rep 8:10382PubMedPubMedCentralGoogle Scholar
  74. 74.
    Kumar A, Tamjar J, Waddell AD, Woodroof HI, Raimi OG, Shaw AM, Peggie M, Muqit MM, van Aalten DM (2017) Structure of PINK1 and mechanisms of Parkinson’s disease associated mutations. eLife 6:e29985PubMedPubMedCentralGoogle Scholar
  75. 75.
    Schubert AF, Gladkova C, Pardon E, Wagstaff JL, Freund SMV, Steyaert J, Maslen SL, Komander D (2017) Structure of PINK1 in complex with its substrate ubiquitin. Nature 552:51–56PubMedPubMedCentralGoogle Scholar
  76. 76.
    Rasool S, Trempe JF (2018) New insights into the structure of PINK1 and the mechanism of ubiquitin phosphorylation. Crit Rev Biochem Mol Biol 53:515–534PubMedGoogle Scholar
  77. 77.
    Morais VA, Haddad D, Craessaerts K, De Bock PJ, Swerts J, Vilain S, Aerts L, Overbergh L, Grunewald A, Seibler P, Klein C, Gevaert K, Verstreken P, De Strooper B (2014) PINK1 loss-of-function mutations affect mitochondrial complex I activity via NdufA10 ubiquinone uncoupling. Science 344:203–207PubMedGoogle Scholar
  78. 78.
    Tsai PI, Lin CH, Hsieh CH, Papakyrikos AM, Kim MJ, Napolioni V, Schoor C, Couthouis J, Wu RM, Wszolek ZK, Winter D, Greicius MD, Ross OA, Wang X (2018) PINK1 phosphorylates MIC60/mitofilin to control structural plasticity of mitochondrial crista junctions. Mol Cell 69(744–756):e746Google Scholar
  79. 79.
    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 105:12022–12027PubMedGoogle Scholar
  80. 80.
    Zhang Y, Wang ZH, Liu Y, Chen Y, Sun N, Gucek M, Zhang F, Xu H (2019) PINK1 inhibits local protein synthesis to limit transmission of deleterious mitochondrial DNA mutations. Mol Cell 73:1127–1137PubMedGoogle Scholar
  81. 81.
    Wenzel DM, Lissounov A, Brzovic PS, Klevit RE (2011) UBCH7 reactivity profile reveals parkin and HHARI to be RING/HECT hybrids. Nature 474:105–108PubMedPubMedCentralGoogle Scholar
  82. 82.
    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 48:245–250PubMedGoogle Scholar
  83. 83.
    Chaugule VK, Burchell L, Barber KR, Sidhu A, Leslie SJ, Shaw GS, Walden H (2011) Autoregulation of Parkin activity through its ubiquitin-like domain. EMBO J 30:2853–2867PubMedPubMedCentralGoogle Scholar
  84. 84.
    Wauer T, Komander D (2013) Structure of the human Parkin ligase domain in an autoinhibited state. EMBO J 32:2099–2112PubMedPubMedCentralGoogle Scholar
  85. 85.
    Trempe JF, Sauvé V, Grenier K, Seirafi M, Tang MY, Menade M, Al-Abdul-Wahid S, Krett J, Wong K, Kozlov G, Nagar B, Fon EA, Gehring K (2013) Structure of parkin reveals mechanisms for ubiquitin ligase activation. Science 340:1451–1455PubMedGoogle Scholar
  86. 86.
    Riley BE, Lougheed JC, Callaway K, Velasquez M, Brecht E, Nguyen L, Shaler T, Walker D, Yang Y, Regnstrom K, Diep L, Zhang Z, Chiou S, Bova M, Artis DR, Yao N, Baker J, Yednock T, Johnston JA (2013) Structure and function of Parkin E3 ubiquitin ligase reveals aspects of RING and HECT ligases. Nat Commun 4:1982PubMedPubMedCentralGoogle Scholar
  87. 87.
    Sauvé V, Lilov A, Seirafi M, Vranas M, Rasool S, Kozlov G, Sprules T, Wang J, Trempe JF, Gehring K (2015) A Ubl/ubiquitin switch in the activation of Parkin. EMBO J 34:2492–2505PubMedPubMedCentralGoogle Scholar
  88. 88.
    Kumar A, Aguirre JD, Condos TE, Martinez-Torres RJ, Chaugule VK, Toth R, Sundaramoorthy R, Mercier P, Knebel A, Spratt DE, Barber KR, Shaw GS, Walden H (2015) Disruption of the autoinhibited state primes the E3 ligase parkin for activation and catalysis. EMBO J 34:2506–2521PubMedPubMedCentralGoogle Scholar
  89. 89.
    Kazlauskaite A, Martinez-Torres RJ, Wilkie S, Kumar A, Peltier J, Gonzalez A, Johnson C, Zhang J, Hope AG, Peggie M, Trost M, van Aalten DM, Alessi DR, Prescott AR, Knebel A, Walden H, Muqit MM (2015) Binding to serine 65-phosphorylated ubiquitin primes Parkin for optimal PINK1-dependent phosphorylation and activation. EMBO Rep 16:939–954PubMedPubMedCentralGoogle Scholar
  90. 90.
    Ordureau A, Sarraf SA, Duda DM, Heo JM, Jedrykowski MP, Sviderskiy VO, Olszewski JL, Koerber JT, Xie T, Beausoleil SA, Wells JA, Gygi SP, Schulman BA, Harper JW (2014) Quantitative proteomics reveal a feedforward mechanism for mitochondrial PARKIN translocation and ubiquitin chain synthesis. Mol Cell 56:360–375PubMedPubMedCentralGoogle Scholar
  91. 91.
    Kumar A, Chaugule VK, Condos TEC, Barber KR, Johnson C, Toth R, Sundaramoorthy R, Knebel A, Shaw GS, Walden H (2017) Parkin-phosphoubiquitin complex reveals cryptic ubiquitin-binding site required for RBR ligase activity. Nat Struct Mol Biol 24:475–483PubMedPubMedCentralGoogle Scholar
  92. 92.
    Wauer T, Simicek M, Schubert A, Komander D (2015) Mechanism of phospho-ubiquitin-induced PARKIN activation. Nature 524:370–374PubMedPubMedCentralGoogle Scholar
  93. 93.
    Yamano K, Queliconi BB, Koyano F, Saeki Y, Hirokawa T, Tanaka K, Matsuda N (2015) Site-specific interaction mapping of phosphorylated ubiquitin to uncover parkin activation. J Biol Chem 290:25199–25211PubMedPubMedCentralGoogle Scholar
  94. 94.
    Aguirre JD, Dunkerley KM, Mercier P, Shaw GS (2017) Structure of phosphorylated UBL domain and insights into PINK1-orchestrated parkin activation. Proc Natl Acad Sci USA 114:298–303PubMedGoogle Scholar
  95. 95.
    Tang MY, Vranas M, Krahn AI, Pundlik S, Trempe JF, Fon EA (2017) Structure-guided mutagenesis reveals a hierarchical mechanism of Parkin activation. Nat Commun 8:14697PubMedPubMedCentralGoogle Scholar
  96. 96.
    Sauvé V, Sung G, Soya N, Kozlov G, Blaimschein N, Miotto L, Trempe JF, Lukacs GL, Gehring K (2018) Mechanism of parkin activation by phosphorylation. Nat Struct Mol Biol 25:623–630PubMedGoogle Scholar
  97. 97.
    Gladkova C, Maslen SL, Skehel JM, Komander D (2018) Mechanism of parkin activation by PINK1. Nature 559:410–414PubMedPubMedCentralGoogle Scholar
  98. 98.
    Kazlauskaite A, Kelly V, Johnson C, Baillie C, Hastie CJ, Peggie M, Macartney T, Woodroof HI, Alessi DR, Pedrioli PG, Muqit MM (2014) Phosphorylation of Parkin at Serine65 is essential for activation: elaboration of a Miro1 substrate-based assay of Parkin E3 ligase activity. Open Biol 4:130213PubMedPubMedCentralGoogle Scholar
  99. 99.
    Fiesel FC, Moussaud-Lamodiere EL, Ando M, Springer W (2014) A specific subset of E2 ubiquitin-conjugating enzymes regulate Parkin activation and mitophagy differently. J Cell Sci 127:3488–3504PubMedPubMedCentralGoogle Scholar
  100. 100.
    Haddad DM, Vilain S, Vos M, Esposito G, Matta S, Kalscheuer VM, Craessaerts K, Leyssen M, Nascimento RM, Vianna-Morgante AM, De Strooper B, Van Esch H, Morais VA, Verstreken P (2013) Mutations in the intellectual disability gene Ube2a cause neuronal dysfunction and impair parkin-dependent mitophagy. Mol Cell 50:831–843PubMedGoogle Scholar
  101. 101.
    Fiesel FC, Ando M, Hudec R, Hill AR, Castanedes-Casey M, Caulfield TR, Moussaud-Lamodiere EL, Stankowski JN, Bauer PO, Lorenzo-Betancor O, Ferrer I, Arbelo JM, Siuda J, Chen L, Dawson VL, Dawson TM, Wszolek ZK, Ross OA, Dickson DW, Springer W (2015) (Patho-)physiological relevance of PINK1-dependent ubiquitin phosphorylation. EMBO Rep 16:1114–1130PubMedPubMedCentralGoogle Scholar
  102. 102.
    Zheng X, Hunter T (2013) Parkin mitochondrial translocation is achieved through a novel catalytic activity coupled mechanism. Cell Res 23:886–897PubMedPubMedCentralGoogle Scholar
  103. 103.
    Okatsu K, Koyano F, Kimura M, Kosako H, Saeki Y, Tanaka K, Matsuda N (2015) Phosphorylated ubiquitin chain is the genuine Parkin receptor. J Cell Biol 209:111–128PubMedPubMedCentralGoogle Scholar
  104. 104.
    Yi W, MacDougall EJ, Tang MY, Krahn AI, Gan-Or Z, Trempe JF, Fon EA (2019) The landscape of Parkin variants reveals pathogenic mechanisms and therapeutic targets in Parkinson’s disease. Hum Mol Genet. CrossRefPubMedGoogle Scholar
  105. 105.
    Imam SZ, Zhou Q, Yamamoto A, Valente AJ, Ali SF, Bains M, Roberts JL, Kahle PJ, Clark RA, Li S (2011) Novel regulation of parkin function through c-Abl-mediated tyrosine phosphorylation: implications for Parkinson’s disease. J Neurosci 31:157–163PubMedPubMedCentralGoogle Scholar
  106. 106.
    Ko HS, Lee Y, Shin JH, Karuppagounder SS, Gadad BS, Koleske AJ, Pletnikova O, Troncoso JC, Dawson VL, Dawson TM (2010) Phosphorylation by the c-Abl protein tyrosine kinase inhibits parkin’s ubiquitination and protective function. Proc Natl Acad Sci USA 107:16691–16696PubMedGoogle Scholar
  107. 107.
    Lee SB, Kim JJ, Nam HJ, Gao B, Yin P, Qin B, Yi SY, Ham H, Evans D, Kim SH, Zhang J, Deng M, Liu T, Zhang H, Billadeau DD, Wang L, Giaime E, Shen J, Pang YP, Jen J, van Deursen JM, Lou Z (2015) Parkin regulates mitosis and genomic stability through Cdc20/Cdh1. Mol Cell 60:21–34PubMedPubMedCentralGoogle Scholar
  108. 108.
    Müller-Rischart AK, Pilsl A, Beaudette P, Patra M, Hadian K, Funke M, Peis R, Deinlein A, Schweimer C, Kuhn PH, Lichtenthaler SF, Motori E, Hrelia S, Wurst W, Trumbach D, Langer T, Krappmann D, Dittmar G, Tatzelt J, Winklhofer KF (2013) The E3 ligase parkin maintains mitochondrial integrity by increasing linear ubiquitination of NEMO. Mol Cell 49:908–921PubMedGoogle Scholar
  109. 109.
    Lazarou M, Narendra DP, Jin SM, Tekle E, Banerjee S, Youle RJ (2013) PINK1 drives Parkin self-association and HECT-like E3 activity upstream of mitochondrial binding. J Cell Biol 200:163–172PubMedPubMedCentralGoogle Scholar
  110. 110.
    Condos TE, Dunkerley KM, Freeman EA, Barber KR, Aguirre JD, Chaugule VK, Xiao Y, Konermann L, Walden H, Shaw GS (2018) Synergistic recruitment of UbcH7~Ub and phosphorylated Ubl domain triggers parkin activation. EMBO J 37:e100014PubMedPubMedCentralGoogle Scholar
  111. 111.
    Ordureau A, Heo JM, Duda DM, Paulo JA, Olszewski JL, Yanishevski D, Rinehart J, Schulman BA, Harper JW (2015) Defining roles of PARKIN and ubiquitin phosphorylation by PINK1 in mitochondrial quality control using a ubiquitin replacement strategy. Proc Natl Acad Sci USA 112:6637–6642PubMedGoogle Scholar
  112. 112.
    Lechtenberg BC, Rajput A, Sanishvili R, Dobaczewska MK, Ware CF, Mace PD, Riedl SJ (2016) Structure of a HOIP/E2~ubiquitin complex reveals RBR E3 ligase mechanism and regulation. Nature 529:546–550PubMedPubMedCentralGoogle Scholar
  113. 113.
    Dove KK, Stieglitz B, Duncan ED, Rittinger K, Klevit RE (2016) Molecular insights into RBR E3 ligase ubiquitin transfer mechanisms. EMBO Rep 17:1221–1235PubMedPubMedCentralGoogle Scholar
  114. 114.
    Dove KK, Olszewski JL, Martino L, Duda DM, Wu XS, Miller DJ, Reiter KH, Rittinger K, Schulman BA, Klevit RE (2017) Structural studies of HHARI/UbcH7 approximately Ub reveal unique E2 approximately Ub conformational restriction by RBR RING1. Structure 25(890–900):e895Google Scholar
  115. 115.
    Stieglitz B, Rana RR, Koliopoulos MG, Morris-Davies AC, Schaeffer V, Christodoulou E, Howell S, Brown NR, Dikic I, Rittinger K (2013) Structural basis for ligase-specific conjugation of linear ubiquitin chains by HOIP. Nature 503:422–426PubMedPubMedCentralGoogle Scholar
  116. 116.
    Tanaka A, Cleland MM, Xu S, Narendra DP, Suen DF, Karbowski M, Youle RJ (2010) Proteasome and p97 mediate mitophagy and degradation of mitofusins induced by Parkin. J Cell Biol 191:1367–1380PubMedPubMedCentralGoogle Scholar
  117. 117.
    Poole AC, Thomas RE, Yu S, Vincow ES, Pallanck L (2010) The mitochondrial fusion-promoting factor mitofusin is a substrate of the PINK1/parkin pathway. PLoS One 5:e10054PubMedPubMedCentralGoogle Scholar
  118. 118.
    Gegg ME, Cooper JM, Chau KY, Rojo M, Schapira AH, Taanman JW (2010) Mitofusin-1 and Mitofusin-2 are ubiquitinated in a PINK1/parkin dependent manner upon induction of mitophagy. Hum Mol Genet 19:4861–4870PubMedPubMedCentralGoogle Scholar
  119. 119.
    Koshiba T, Detmer SA, Kaiser JT, Chen H, McCaffery JM, Chan DC (2004) Structural basis of mitochondrial tethering by mitofusin complexes. Science 305:858–862PubMedGoogle Scholar
  120. 120.
    de Brito OM, Scorrano L (2008) Mitofusin 2 tethers endoplasmic reticulum to mitochondria. Nature 456:605–610PubMedGoogle Scholar
  121. 121.
    McLelland GL, Goiran T, Yi W, Dorval G, Chen CX, Lauinger ND, Krahn AI, Valimehr S, Rakovic A, Rouiller I, Durcan TM, Trempe JF, Fon EA (2018) Mfn2 ubiquitination by PINK1/parkin gates the p97-dependent release of ER from mitochondria to drive mitophagy. eLife 7:e32866PubMedPubMedCentralGoogle Scholar
  122. 122.
    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 20:1726–1737PubMedPubMedCentralGoogle Scholar
  123. 123.
    Wang X, Winter D, Ashrafi G, Schlehe J, Wong YL, Selkoe D, Rice S, Steen J, Lavoie MJ, Schwarz TL (2011) PINK1 and Parkin target miro for phosphorylation and degradation to arrest mitochondrial motility. Cell 147:893–906PubMedPubMedCentralGoogle Scholar
  124. 124.
    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 496:372–376PubMedPubMedCentralGoogle Scholar
  125. 125.
    Chen Y, Dorn GW 2nd (2013) PINK1-phosphorylated mitofusin 2 is a Parkin receptor for culling damaged mitochondria. Science 340:471–475PubMedPubMedCentralGoogle Scholar
  126. 126.
    Rakovic A, Shurkewitsch K, Seibler P, Grunewald A, Zanon A, Hagenah J, Krainc D, Klein C (2013) Phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1)-dependent ubiquitination of endogenous Parkin attenuates mitophagy: study in human primary fibroblasts and induced pluripotent stem cell-derived neurons. J Biol Chem 288:2223–2237PubMedGoogle Scholar
  127. 127.
    Bertolin G, Jacoupy M, Traver S, Ferrando-Miguel R, Saint Georges T, Grenier K, Ardila-Osorio H, Muriel MP, Takahashi H, Lees AJ, Gautier C, Guedin D, Coge F, Fon EA, Brice A, Corti O (2015) Parkin maintains mitochondrial levels of the protective Parkinson’s disease-related enzyme 17-beta hydroxysteroid dehydrogenase type 10. Cell Death Differ 22:1563–1576PubMedPubMedCentralGoogle Scholar
  128. 128.
    Gelmetti V, De Rosa P, Torosantucci L, Marini ES, Romagnoli A, Di Rienzo M, Arena G, Vignone D, Fimia GM, Valente EM (2017) PINK1 and BECN1 relocalize at mitochondria-associated membranes during mitophagy and promote ER-mitochondria tethering and autophagosome formation. Autophagy 13:654–669PubMedPubMedCentralGoogle Scholar
  129. 129.
    Narendra DP, Kane LA, Hauser DN, Fearnley IM, Youle RJ (2010) p62/SQSTM1 is required for Parkin-induced mitochondrial clustering but not mitophagy; VDAC1 is dispensable for both. Autophagy 6:1090–1106PubMedPubMedCentralGoogle Scholar
  130. 130.
    van Wijk SJ, Fiskin E, Putyrski M, Pampaloni F, Hou J, Wild P, Kensche T, Grecco HE, Bastiaens P, Dikic I (2012) Fluorescence-based sensors to monitor localization and functions of linear and K63-linked ubiquitin chains in cells. Mol Cell 47:797–809PubMedPubMedCentralGoogle Scholar
  131. 131.
    Durcan TM, Tang MY, Perusse JR, Dashti EA, Aguileta MA, McLelland GL, Gros P, Shaler TA, Faubert D, Coulombe B, Fon EA (2014) USP8 regulates mitophagy by removing K6-linked ubiquitin conjugates from parkin. EMBO J 33:2473–2491PubMedPubMedCentralGoogle Scholar
  132. 132.
    Husnjak K, Elsasser S, Zhang N, Chen X, Randles L, Shi Y, Hofmann K, Walters KJ, Finley D, Dikic I (2008) Proteasome subunit Rpn13 is a novel ubiquitin receptor. Nature 453:481–488PubMedPubMedCentralGoogle Scholar
  133. 133.
    Verma R, Oania R, Graumann J, Deshaies RJ (2004) Multiubiquitin chain receptors define a layer of substrate selectivity in the ubiquitin-proteasome system. Cell 118:99–110PubMedGoogle Scholar
  134. 134.
    Wilkinson CR, Seeger M, Hartmann-Petersen R, Stone M, Wallace M, Semple C, Gordon C (2001) Proteins containing the UBA domain are able to bind to multi-ubiquitin chains. Nat Cell Biol 3:939–943PubMedGoogle Scholar
  135. 135.
    Lazarou M, Sliter DA, Kane LA, Sarraf SA, Wang C, Burman JL, Sideris DP, Fogel AI, Youle RJ (2015) The ubiquitin kinase PINK1 recruits autophagy receptors to induce mitophagy. Nature 524:309–314PubMedPubMedCentralGoogle Scholar
  136. 136.
    Aguileta MA, Korac J, Durcan TM, Trempe JF, Haber M, Gehring K, Elsasser S, Waidmann O, Fon EA, Husnjak K (2015) The E3 ubiquitin ligase parkin is recruited to the 26 S proteasome via the proteasomal ubiquitin receptor Rpn13. J Biol Chem 290:7492–7505PubMedPubMedCentralGoogle Scholar
  137. 137.
    Wong YC, Holzbaur EL (2014) Optineurin is an autophagy receptor for damaged mitochondria in parkin-mediated mitophagy that is disrupted by an ALS-linked mutation. Proc Natl Acad Sci USA 111:E4439–E4448PubMedGoogle Scholar
  138. 138.
    Okatsu K, Saisho K, Shimanuki M, Nakada K, Shitara H, Sou YS, Kimura M, Sato S, Hattori N, Komatsu M, Tanaka K, Matsuda N (2010) p62/SQSTM1 cooperates with Parkin for perinuclear clustering of depolarized mitochondria. Genes Cells 15:887–900PubMedPubMedCentralGoogle Scholar
  139. 139.
    Randow F, Youle RJ (2014) Self and nonself: how autophagy targets mitochondria and bacteria. Cell Host Microbe 15:403–411PubMedPubMedCentralGoogle Scholar
  140. 140.
    Heo JM, Ordureau A, Paulo JA, Rinehart J, Harper JW (2015) The PINK1-PARKIN mitochondrial ubiquitylation pathway drives a program of OPTN/NDP52 recruitment and TBK1 activation to promote mitophagy. Mol Cell 60:7–20PubMedPubMedCentralGoogle Scholar
  141. 141.
    Gersch M, Gladkova C, Schubert AF, Michel MA, Maslen S, Komander D (2017) Mechanism and regulation of the Lys6-selective deubiquitinase USP30. Nat Struct Mol Biol 24:920–930PubMedPubMedCentralGoogle Scholar
  142. 142.
    Yamano K, Wang C, Sarraf SA, Munch C, Kikuchi R, Noda NN, Hizukuri Y, Kanemaki MT, Harper W, Tanaka K, Matsuda N, Youle RJ (2018) Endosomal Rab cycles regulate Parkin-mediated mitophagy. eLife 7:e31326PubMedPubMedCentralGoogle Scholar
  143. 143.
    Yamano K, Fogel AI, Wang C, van der Bliek AM, Youle RJ (2014) Mitochondrial Rab GAPs govern autophagosome biogenesis during mitophagy. eLife 3:e01612PubMedPubMedCentralGoogle Scholar
  144. 144.
    Durcan TM, Kontogiannea M, Bedard N, Wing SS, Fon EA (2012) Ataxin-3 deubiquitination is coupled to Parkin ubiquitination via E2 ubiquitin-conjugating enzyme. J Biol Chem 287:531–541PubMedGoogle Scholar
  145. 145.
    Durcan TM, Kontogiannea M, Thorarinsdottir T, Fallon L, Williams AJ, Djarmati A, Fantaneanu T, Paulson HL, Fon EA (2011) The Machado–Joseph disease-associated mutant form of ataxin-3 regulates parkin ubiquitination and stability. Hum Mol Genet 20:141–154PubMedGoogle Scholar
  146. 146.
    Bingol B, Tea JS, Phu L, Reichelt M, Bakalarski CE, Song Q, Foreman O, Kirkpatrick DS, Sheng M (2014) The mitochondrial deubiquitinase USP30 opposes parkin-mediated mitophagy. Nature 510:370–375PubMedGoogle Scholar
  147. 147.
    Wang Y, Serricchio M, Jauregui M, Shanbhag R, Stoltz T, Di Paolo CT, Kim PK, McQuibban GA (2015) Deubiquitinating enzymes regulate PARK2-mediated mitophagy. Autophagy 11:595–606PubMedPubMedCentralGoogle Scholar
  148. 148.
    Sato Y, Okatsu K, Saeki Y, Yamano K, Matsuda N, Kaiho A, Yamagata A, Goto-Ito S, Ishikawa M, Hashimoto Y, Tanaka K, Fukai S (2017) Structural basis for specific cleavage of Lys6-linked polyubiquitin chains by USP30. Nat Struct Mol Biol 24:911–919PubMedGoogle Scholar
  149. 149.
    Marcassa E, Kallinos A, Jardine J, Rusilowicz-Jones EV, Martinez A, Kuehl S, Islinger M, Clague MJ, Urbe S (2018) Dual role of USP30 in controlling basal pexophagy and mitophagy. EMBO Rep 19:e45595PubMedPubMedCentralGoogle Scholar
  150. 150.
    Cornelissen T, Haddad D, Wauters F, Van Humbeeck C, Mandemakers W, Koentjoro B, Sue C, Gevaert K, De Strooper B, Verstreken P, Vandenberghe W (2014) The deubiquitinase USP15 antagonizes Parkin-mediated mitochondrial ubiquitination and mitophagy. Hum Mol Genet 23:5227–5242PubMedGoogle Scholar
  151. 151.
    Cornelissen T, Vilain S, Vints K, Gounko N, Verstreken P, Vandenberghe W (2018) Deficiency of parkin and PINK1 impairs age-dependent mitophagy in Drosophila. eLife 7:e35878PubMedPubMedCentralGoogle Scholar
  152. 152.
    Liu X, Hebron M, Shi W, Lonskaya I, Moussa CE (2019) Ubiquitin specific protease-13 independently regulates parkin ubiquitination and alpha-synuclein clearance in alpha-synucleinopathies. Hum Mol Genet 28:548–560PubMedGoogle Scholar
  153. 153.
    Yang JY, Yang WY (2013) Bit-by-bit autophagic removal of parkin-labelled mitochondria. Nat Commun 4:2428PubMedGoogle Scholar
  154. 154.
    Ashrafi G, Schlehe JS, LaVoie MJ, Schwarz TL (2014) Mitophagy of damaged mitochondria occurs locally in distal neuronal axons and requires PINK1 and Parkin. J Cell Biol 206:655–670PubMedPubMedCentralGoogle Scholar
  155. 155.
    McWilliams TG, Prescott AR, Montava-Garriga L, Ball G, Singh F, Barini E, Muqit MMK, Brooks SP, Ganley IG (2018) Basal mitophagy occurs independently of PINK1 in mouse tissues of high metabolic demand. Cell Metab 27(439–449):e435Google Scholar
  156. 156.
    Kitada T, Pisani A, Porter DR, Yamaguchi H, Tscherter A, Martella G, Bonsi P, Zhang C, Pothos EN, Shen J (2007) Impaired dopamine release and synaptic plasticity in the striatum of PINK1-deficient mice. Proc Natl Acad Sci USA 104:11441–11446PubMedGoogle Scholar
  157. 157.
    McWilliams TG, Barini E, Pohjolan-Pirhonen R, Brooks SP, Singh F, Burel S, Balk K, Kumar A, Montava-Garriga L, Prescott AR, Hassoun SM, Mouton-Liger F, Ball G, Hills R, Knebel A, Ulusoy A, Di Monte DA, Tamjar J, Antico O, Fears K, Smith L, Brambilla R, Palin E, Valori M, Eerola-Rautio J, Tienari P, Corti O, Dunnett SB, Ganley IG, Suomalainen A, Muqit MMK (2018) Phosphorylation of Parkin at serine 65 is essential for its activation in vivo. Open Biol 8:180108PubMedPubMedCentralGoogle Scholar
  158. 158.
    Hou X, Fiesel FC, Truban D, Castanedes Casey M, Lin WL, Soto AI, Tacik P, Rousseau LG, Diehl NN, Heckman MG, Lorenzo-Betancor O, Ferrer I, Arbelo JM, Steele JC, Farrer MJ, Cornejo-Olivas M, Torres L, Mata IF, Graff-Radford NR, Wszolek ZK, Ross OA, Murray ME, Dickson DW, Springer W (2018) Age- and disease-dependent increase of the mitophagy marker phospho-ubiquitin in normal aging and Lewy body disease. Autophagy 14:1404–1418PubMedPubMedCentralGoogle Scholar
  159. 159.
    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 70:190–203PubMedGoogle Scholar
  160. 160.
    Vincow ES, Merrihew G, Thomas RE, Shulman NJ, Beyer RP, Maccoss MJ, Pallanck LJ (2013) The PINK1-Parkin pathway promotes both mitophagy and selective respiratory chain turnover in vivo. Proc Natl Acad Sci USA 110:6400–6405PubMedGoogle Scholar
  161. 161.
    Soubannier V, McLelland GL, Zunino R, Braschi E, Rippstein P, Fon EA, McBride HM (2012) A vesicular transport pathway shuttles cargo from mitochondria to lysosomes. Curr Biol 22:135–141PubMedGoogle Scholar
  162. 162.
    McLelland GL, Lee SA, McBride HM, Fon EA (2016) Syntaxin-17 delivers PINK1/parkin-dependent mitochondrial vesicles to the endolysosomal system. J Cell Biol 214:275–291PubMedPubMedCentralGoogle Scholar
  163. 163.
    de Castro IP, Costa AC, Celardo I, Tufi R, Dinsdale D, Loh SH, Martins LM (2013) Drosophila ref(2)P is required for the parkin-mediated suppression of mitochondrial dysfunction in pink1 mutants. Cell Death Dis 4:e873PubMedPubMedCentralGoogle Scholar
  164. 164.
    Greene JC, Whitworth AJ, Andrews LA, Parker TJ, Pallanck LJ (2005) Genetic and genomic studies of Drosophila parkin mutants implicate oxidative stress and innate immune responses in pathogenesis. Hum Mol Genet 14:799–811PubMedGoogle Scholar
  165. 165.
    Witoelar A, Jansen IE, Wang Y, Desikan RS, Gibbs JR, Blauwendraat C, Thompson WK, Hernandez DG, Djurovic S, Schork AJ, Bettella F, Ellinghaus D, Franke A, Lie BA, McEvoy LK, Karlsen TH, Lesage S, Morris HR, Brice A, Wood NW, Heutink P, Hardy J, Singleton AB, Dale AM, Gasser T, Andreassen OA, Sharma M, International Parkinson’s Disease Genomics Consortium NABEC, United Kingdom Brain Expression Consortium I (2017) Genome-wide pleiotropy between Parkinson disease and autoimmune diseases. JAMA Neurol 74:780–792PubMedPubMedCentralGoogle Scholar
  166. 166.
    Steger M, Tonelli F, Ito G, Davies P, Trost M, Vetter M, Wachter S, Lorentzen E, Duddy G, Wilson S, Baptista MA, Fiske BK, Fell MJ, Morrow JA, Reith AD, Alessi DR, Mann M (2016) Phosphoproteomics reveals that Parkinson’s disease kinase LRRK2 regulates a subset of Rab GTPases. eLife 5:e12813PubMedPubMedCentralGoogle Scholar
  167. 167.
    Li XD, Wu J, Gao D, Wang H, Sun L, Chen ZJ (2013) Pivotal roles of cGAS-cGAMP signaling in antiviral defense and immune adjuvant effects. Science 341:1390–1394PubMedGoogle Scholar
  168. 168.
    Zhang FR, Huang W, Chen SM, Sun LD, Liu H, Li Y, Cui Y, Yan XX, Yang HT, Yang RD, Chu TS, Zhang C, Zhang L, Han JW, Yu GQ, Quan C, Yu YX, Zhang Z, Shi BQ, Zhang LH, Cheng H, Wang CY, Lin Y, Zheng HF, Fu XA, Zuo XB, Wang Q, Long H, Sun YP, Cheng YL, Tian HQ, Zhou FS, Liu HX, Lu WS, He SM, Du WL, Shen M, Jin QY, Wang Y, Low HQ, Erwin T, Yang NH, Li JY, Zhao X, Jiao YL, Mao LG, Yin G, Jiang ZX, Wang XD, Yu JP, Hu ZH, Gong CH, Liu YQ, Liu RY, Wang DM, Wei D, Liu JX, Cao WK, Cao HZ, Li YP, Yan WG, Wei SY, Wang KJ, Hibberd ML, Yang S, Zhang XJ, Liu JJ (2009) Genome-wide association study of leprosy. N Engl J Med 361:2609–2618PubMedGoogle Scholar
  169. 169.
    West AB, Lockhart PJ, O’Farell C, Farrer MJ (2003) Identification of a novel gene linked to parkin via a bi-directional promoter. J Mol Biol 326:11–19PubMedGoogle Scholar
  170. 170.
    Ikeda T (2008) Parkin-co-regulated gene (PACRG) product interacts with tubulin and microtubules. FEBS Lett 582:1413–1418PubMedGoogle Scholar
  171. 171.
    Ikeda K, Ikeda T, Morikawa K, Kamiya R (2007) Axonemal localization of Chlamydomonas PACRG, a homologue of the human Parkin-coregulated gene product. Cell Motil Cytoskelet 64:814–821Google Scholar
  172. 172.
    Loucks CM, Bialas NJ, Dekkers MP, Walker DS, Grundy LJ, Li C, Inglis PN, Kida K, Schafer WR, Blacque OE, Jansen G, Leroux MR (2016) PACRG, a protein linked to ciliary motility, mediates cellular signaling. Mol Biol Cell 27:2133–2144PubMedPubMedCentralGoogle Scholar
  173. 173.
    Guemez-Gamboa A, Coufal NG, Gleeson JG (2014) Primary cilia in the developing and mature brain. Neuron 82:511–521PubMedPubMedCentralGoogle Scholar
  174. 174.
    Wilson GR, Tan JT, Brody KM, Taylor JM, Delatycki MB, Lockhart PJ (2009) Expression and localization of the Parkin co-regulated gene in mouse CNS suggests a role in ependymal cilia function. Neurosci Lett 460:97–101PubMedGoogle Scholar
  175. 175.
    Lorenzetti D, Bishop CE, Justice MJ (2004) Deletion of the Parkin coregulated gene causes male sterility in the quaking(viable) mouse mutant. Proc Natl Acad Sci USA 101:8402–8407PubMedGoogle Scholar
  176. 176.
    Steger M, Diez F, Dhekne HS, Lis P, Nirujogi RS, Karayel O, Tonelli F, Martinez TN, Lorentzen E, Pfeffer SR, Alessi DR, Mann M (2017) Systematic proteomic analysis of LRRK2-mediated Rab GTPase phosphorylation establishes a connection to ciliogenesis. eLife 6:e31012PubMedPubMedCentralGoogle Scholar
  177. 177.
    Dhekne HS, Yanatori I, Gomez RC, Tonelli F, Diez F, Schule B, Steger M, Alessi DR, Pfeffer SR (2018) A pathway for Parkinson’s disease LRRK2 kinase to block primary cilia and Sonic hedgehog signaling in the brain. eLife 7:e40202PubMedPubMedCentralGoogle Scholar
  178. 178.
    Lai YC, Kondapalli C, Lehneck R, Procter JB, Dill BD, Woodroof HI, Gourlay R, Peggie M, Macartney TJ, Corti O, Corvol JC, Campbell DG, Itzen A, Trost M, Muqit MM (2015) Phosphoproteomic screening identifies Rab GTPases as novel downstream targets of PINK1. EMBO J 34:2840–2861PubMedPubMedCentralGoogle Scholar
  179. 179.
    Wong YC, Ysselstein D, Krainc D (2018) Mitochondria–lysosome contacts regulate mitochondrial fission via RAB7 GTP hydrolysis. Nature 554:382–386PubMedPubMedCentralGoogle Scholar
  180. 180.
    Gallop JL, Butler PJ, McMahon HT (2005) Endophilin and CtBP/BARS are not acyl transferases in endocytosis or Golgi fission. Nature 438:675–678PubMedGoogle Scholar
  181. 181.
    Micheva KD, Kay BK, McPherson PS (1997) Synaptojanin forms two separate complexes in the nerve terminal. Interactions with endophilin and amphiphysin. J Biol Chem 272:27239–27245PubMedGoogle Scholar
  182. 182.
    Sparks AB, Hoffman NG, McConnell SJ, Fowlkes DM, Kay BK (1996) Cloning of ligand targets: systematic isolation of SH3 domain-containing proteins. Nat Biotechnol 14:741–744PubMedGoogle Scholar
  183. 183.
    Quadri M, Fang M, Picillo M, Olgiati S, Breedveld GJ, Graafland J, Wu B, Xu F, Erro R, Amboni M, Pappata S, Quarantelli M, Annesi G, Quattrone A, Chien HF, Barbosa ER, The International Parkinsonism Genetics Network, Oostra BA, Barone P, Wang J, Bonifati V (2013) Mutation in the SYNJ1 gene associated with autosomal recessive, early-onset parkinsonism. Hum Mutat 34:1208–1215PubMedGoogle Scholar
  184. 184.
    Krebs CE, Karkheiran S, Powell JC, Cao M, Makarov V, Darvish H, Di Paolo G, Walker RH, Shahidi GA, Buxbaum JD, De Camilli P, Yue Z, Paisan-Ruiz C (2013) The Sac1 domain of SYNJ1 identified mutated in a family with early-onset progressive parkinsonism with generalized seizures. Hum Mutat 34:1200–1207PubMedPubMedCentralGoogle Scholar
  185. 185.
    Chang D, Nalls MA, Hallgrimsdottir IB, Hunkapiller J, van der Brug M, Cai F, International Parkinson’s Disease Genomics Consortium, The 23andMe Research Team, Kerchner GA, Ayalon G, Bingol B, Sheng M, Hinds D, Behrens TW, Singleton AB, Bhangale TR, Graham RR (2017) A meta-analysis of genome-wide association studies identifies 17 new Parkinson’s disease risk loci. Nat Genet 49:1511–1516PubMedPubMedCentralGoogle Scholar
  186. 186.
    Nalls MA, Blauwendraat C, Vallerga CL, Heilbron K, Bandres-CIga S, Chang D, Tan M, Kia DA, Noyce AJ, Xue A, Bras J, Young E, Von Coelln R, Simon-Sanchez J, Schulte C, Sharma M, Krohn L, Pihlstrom L, Siitonen A, Iwaki H, Leonard H, Faghri F, Gibbs R, Hernandez DG, Scholz SW, Botia JA, Martinez M, Corvol JC, Lesage S, Jankovic J, Shulman LM, The 23andMe Research Team, System Genomics of Parkinson’s Disease (SGPD) Consortium, Sutherland M, Tienari P, Majamaa K, Toft M, Andreassen OA, Bangale T, Brice A, Yang J, Gan-Or Z, Gasser T, Heutink P, Shulman JM, Wood N, Hinds DA, Hardy JA, Morris HR, Gratten J, Visscher PM, Graham RR, Singleton AB (2019) Expanding Parkinson’s disease genetics: novel risk loci, genomic context, causal insights and heritable risk. BioRxiv. CrossRefGoogle Scholar
  187. 187.
    Cao M, Milosevic I, Giovedi S, De Camilli P (2014) Upregulation of parkin in endophilin mutant mice. J Neurosci 34:16544–16549PubMedPubMedCentralGoogle Scholar
  188. 188.
    Soukup SF, Kuenen S, Vanhauwaert R, Manetsberger J, Hernandez-Diaz S, Swerts J, Schoovaerts N, Vilain S, Gounko NV, Vints K, Geens A, De Strooper B, Verstreken P (2016) A LRRK2-dependent endophilina phosphoswitch is critical for macroautophagy at presynaptic terminals. Neuron 92:829–844PubMedGoogle Scholar
  189. 189.
    Matta S, Van Kolen K, da Cunha R, van den Bogaart G, Mandemakers W, Miskiewicz K, De Bock PJ, Morais VA, Vilain S, Haddad D, Delbroek L, Swerts J, Chavez-Gutierrez L, Esposito G, Daneels G, Karran E, Holt M, Gevaert K, Moechars DW, De Strooper B, Verstreken P (2012) LRRK2 controls an EndoA phosphorylation cycle in synaptic endocytosis. Neuron 75:1008–1021PubMedGoogle Scholar
  190. 190.
    Periquet M, Corti O, Jacquier S, Brice A (2005) Proteomic analysis of parkin knockout mice: alterations in energy metabolism, protein handling and synaptic function. J Neurochem 95:1259–1276PubMedGoogle Scholar
  191. 191.
    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 299:256–259PubMedGoogle Scholar
  192. 192.
    Hauser DN, Mamais A, Conti MM, Primiani CT, Kumaran R, Dillman AA, Langston RG, Beilina A, Garcia JH, Diaz-Ruiz A, Bernier M, Fiesel FC, Hou X, Springer W, Li Y, de Cabo R, Cookson MR (2017) Hexokinases link DJ-1 to the PINK1/parkin pathway. Mol Neurodegener 12:70PubMedPubMedCentralGoogle Scholar
  193. 193.
    Joselin AP, Hewitt SJ, Callaghan SM, Kim RH, Chung YH, Mak TW, Shen J, Slack RS, Park DS (2012) ROS-dependent regulation of Parkin and DJ-1 localization during oxidative stress in neurons. Hum Mol Genet 21:4888–4903PubMedGoogle Scholar
  194. 194.
    Thomas KJ, McCoy MK, Blackinton J, Beilina A, van der Brug M, Sandebring A, Miller D, Maric D, Cedazo-Minguez A, Cookson MR (2011) DJ-1 acts in parallel to the PINK1/parkin pathway to control mitochondrial function and autophagy. Hum Mol Genet 20:40–50PubMedGoogle Scholar
  195. 195.
    Matsuda N, Kimura M, Queliconi BB, Kojima W, Mishima M, Takagi K, Koyano F, Yamano K, Mizushima T, Ito Y, Tanaka K (2017) Parkinson’s disease-related DJ-1 functions in thiol quality control against aldehyde attack in vitro. Sci Rep 7:12816PubMedPubMedCentralGoogle Scholar
  196. 196.
    Lee JY, Song J, Kwon K, Jang S, Kim C, Baek K, Kim J, Park C (2012) Human DJ-1 and its homologs are novel glyoxalases. Hum Mol Genet 21:3215–3225PubMedGoogle Scholar
  197. 197.
    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:e327PubMedPubMedCentralGoogle Scholar
  198. 198.
    Guzman JN, Sanchez-Padilla J, Wokosin D, Kondapalli J, Ilijic E, Schumacker PT, Surmeier DJ (2010) Oxidant stress evoked by pacemaking in dopaminergic neurons is attenuated by DJ-1. Nature 468:696–700PubMedPubMedCentralGoogle Scholar
  199. 199.
    Pacelli C, Giguere N, Bourque MJ, Levesque M, Slack RS, Trudeau LE (2015) Elevated mitochondrial bioenergetics and axonal arborization size are key contributors to the vulnerability of dopamine neurons. Curr Biol 25:2349–2360PubMedGoogle Scholar
  200. 200.
    Liss B, Striessnig J (2019) The potential of L-type calcium channels as a drug target for neuroprotective therapy in Parkinson’s disease. Annu Rev Pharmacol Toxicol 59:263–289PubMedGoogle Scholar
  201. 201.
    Gautier CA, Erpapazoglou Z, Mouton-Liger F, Muriel MP, Cormier F, Bigou S, Duffaure S, Girard M, Foret B, Iannielli A, Broccoli V, Dalle C, Bohl D, Michel PP, Corvol JC, Brice A, Corti O (2016) The endoplasmic reticulum-mitochondria interface is perturbed in PARK2 knockout mice and patients with PARK2 mutations. Hum Mol Genet 25:2972–2984PubMedGoogle Scholar
  202. 202.
    Basso V, Marchesan E, Peggion C, Chakraborty J, von Stockum S, Giacomello M, Ottolini D, Debattisti V, Caicci F, Tasca E, Pegoraro V, Angelini C, Antonini A, Bertoli A, Brini M, Ziviani E (2018) Regulation of endoplasmic reticulum–mitochondria contacts by Parkin via Mfn2. Pharmacol Res 138:43–56PubMedGoogle Scholar
  203. 203.
    Hertz NT, Berthet A, Sos ML, Thorn KS, Burlingame AL, Nakamura K, Shokat KM (2013) A neo-substrate that amplifies catalytic activity of Parkinson’s-disease-related kinase PINK1. Cell 154:737–747PubMedPubMedCentralGoogle Scholar
  204. 204.
    Kluge AF, Lagu BR, Maiti P, Jaleel M, Webb M, Malhotra J, Mallat A, Srinivas PA, Thompson JE (2018) Novel highly selective inhibitors of ubiquitin specific protease 30 (USP30) accelerate mitophagy. Bioorg Med Chem Lett 28:2655–2659PubMedGoogle Scholar
  205. 205.
    Teyra J, Singer AU, Schmitges FW, Jaynes P, Kit Leng Lui S, Polyak MJ, Fodil N, Krieger JR, Tong J, Schwerdtfeger C, Brasher BB, Ceccarelli DFJ, Moffat J, Sicheri F, Moran MF, Gros P, Eichhorn PJA, Lenter M, Boehmelt G, Sidhu SS (2019) Structural and functional characterization of ubiquitin variant inhibitors of USP15. Structure 27:590–605PubMedGoogle Scholar
  206. 206.
    Torre S, Polyak MJ, Langlais D, Fodil N, Kennedy JM, Radovanovic I, Berghout J, Leiva-Torres GA, Krawczyk CM, Ilangumaran S, Mossman K, Liang C, Knobeloch KP, Healy LM, Antel J, Arbour N, Prat A, Majewski J, Lathrop M, Vidal SM, Gros P (2017) USP15 regulates type I interferon response and is required for pathogenesis of neuroinflammation. Nat Immunol 18:54–63PubMedGoogle Scholar
  207. 207.
    Vincent J, Adura C, Gao P, Luz A, Lama L, Asano Y, Okamoto R, Imaeda T, Aida J, Rothamel K, Gogakos T, Steinberg J, Reasoner S, Aso K, Tuschl T, Patel DJ, Glickman JF, Ascano M (2017) Small molecule inhibition of cGAS reduces interferon expression in primary macrophages from autoimmune mice. Nat Commun 8:750PubMedPubMedCentralGoogle Scholar
  208. 208.
    Cesari R, Martin ES, Calin GA, Pentimalli F, Bichi R, McAdams H, Trapasso F, Drusco A, Shimizu M, Masciullo V, D’Andrilli G, Scambia G, Picchio MC, Alder H, Godwin AK, Croce CM (2003) Parkin, a gene implicated in autosomal recessive juvenile parkinsonism, is a candidate tumor suppressor gene on chromosome 6q25-q27. Proc Natl Acad Sci USA 100:5956–5961PubMedGoogle Scholar
  209. 209.
    Lin DC, Xu L, Chen Y, Yan H, Hazawa M, Doan N, Said JW, Ding LW, Liu LZ, Yang H, Yu S, Kahn M, Yin D, Koeffler HP (2015) Genomic and functional analysis of the E3 ligase PARK2 in glioma. Cancer Res 75:1815–1827PubMedPubMedCentralGoogle Scholar
  210. 210.
    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 24:197–211PubMedGoogle Scholar
  211. 211.
    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 302:841PubMedPubMedCentralGoogle Scholar
  212. 212.
    Di Maio R, Barrett PJ, Hoffman EK, Barrett CW, Zharikov A, Borah A, Hu X, McCoy J, Chu CT, Burton EA, Hastings TG, Greenamyre JT (2016) alpha-Synuclein binds to TOM20 and inhibits mitochondrial protein import in Parkinson’s disease. Sci Transl Med 8:342ra378Google Scholar
  213. 213.
    Kamp F, Exner N, Lutz AK, Wender N, Hegermann J, Brunner B, Nuscher B, Bartels T, Giese A, Beyer K, Eimer S, Winklhofer KF, Haass C (2010) Inhibition of mitochondrial fusion by alpha-synuclein is rescued by PINK1, Parkin and DJ-1. EMBO J 29:3571–3589PubMedPubMedCentralGoogle Scholar
  214. 214.
    Ryan T, Bamm VV, Stykel MG, Coackley CL, Humphries KM, Jamieson-Williams R, Ambasudhan R, Mosser DD, Lipton SA, Harauz G, Ryan SD (2018) Cardiolipin exposure on the outer mitochondrial membrane modulates alpha-synuclein. Nat Commun 9:817PubMedPubMedCentralGoogle Scholar
  215. 215.
    Mazzulli JR, Zunke F, Isacson O, Studer L, Krainc D (2016) alpha-Synuclein-induced lysosomal dysfunction occurs through disruptions in protein trafficking in human midbrain synucleinopathy models. Proc Natl Acad Sci USA 113:1931–1936PubMedGoogle Scholar
  216. 216.
    Minakaki G, Menges S, Kittel A, Emmanouilidou E, Schaeffner I, Barkovits K, Bergmann A, Rockenstein E, Adame A, Marxreiter F, Mollenhauer B, Galasko D, Buzas EI, Schlotzer-Schrehardt U, Marcus K, Xiang W, Lie DC, Vekrellis K, Masliah E, Winkler J, Klucken J (2018) Autophagy inhibition promotes SNCA/alpha-synuclein release and transfer via extracellular vesicles with a hybrid autophagosome-exosome-like phenotype. Autophagy 14:98–119PubMedPubMedCentralGoogle Scholar
  217. 217.
    Hoffmann AC, Minakaki G, Menges S, Salvi R, Savitskiy S, Kazman A, Vicente Miranda H, Mielenz D, Klucken J, Winkler J, Xiang W (2019) Extracellular aggregated alpha synuclein primarily triggers lysosomal dysfunction in neural cells prevented by trehalose. Sci Rep 9:544PubMedPubMedCentralGoogle Scholar
  218. 218.
    Ruskey JA, Zhou S, Santiago R, Franche LA, Alam A, Ronciere L, Spiegelman D, Fon EA, Trempe JF, Kalia LV, Postuma RB, Dupre N, Rivard GE, Assouline S, Amato D, Gan-Or Z (2018) The GBA p.Trp378Gly mutation is a probable French-Canadian founder mutation causing Gaucher disease and synucleinopathies. Clin Genet 94:339–345PubMedGoogle Scholar
  219. 219.
    Alcalay RN, Mallett V, Vanderperre B, Tavassoly O, Dauvilliers Y, Wu RYJ, Ruskey JA, Leblond CS, Ambalavanan A, Laurent SB, Spiegelman D, Dionne-Laporte A, Liong C, Levy OA, Fahn S, Waters C, Kuo SH, Chung WK, Ford B, Marder KS, Kang UJ, Hassin-Baer S, Greenbaum L, Trempe JF, Wolf P, Oliva P, Zhang XK, Clark LN, Langlois M, Dion PA, Fon EA, Dupre N, Rouleau GA, Gan-Or Z (2019) SMPD1 mutations, activity, and alpha-synuclein accumulation in Parkinson’s disease. Mov Disord 34:526–535PubMedGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of Pharmacology and Therapeutics and Centre for Structural BiologyMcGill UniversityMontrealCanada

Personalised recommendations