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Parkin-associated Parkinson’s disease

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Abstract

Mutations in the PARK2 gene coding for parkin cause autosomal recessive juvenile parkinsonism (AR-JP), a familial form of Parkinson’s disease (PD). Parkin functions as an E3 ubiquitin ligase, and loss of this ubiquitin ligase activity appears to be the mechanism underlying pathogenesis of AR-JP. Recently, the spectrum of genetic, clinical, and pathological findings on AR-JP has been significantly expanded. Moreover, a considerable number of parkin interactors and/or substrates have been identified and characterized, and animal models of parkin deficiency have been generated. In this review, we provide an overview of the most relevant findings and discuss their implications for the pathogenesis of AR-JP and sporadic PD.

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References

  • Abbas N, Lucking CB, Ricard S, Durr A, Bonifati V, De Michele G, Bouley S, Vaughan JR, Gasser T, Marconi R, Broussolle E, Brefel-Courbon C, Harhangi BS, Oostra BA, Fabrizio E, Bohme GA, Pradier L, Wood NW, Filla A, Meco G, Denefle P, Agid Y, Brice A (1999) A wide variety of mutations in the parkin gene are responsible for autosomal recessive parkinsonism in Europe. French Parkinson’s Disease Genetics Study Group and the European Consortium on Genetic Susceptibility in Parkinson’s Disease. Hum Mol Genet 8:567–574

    Article  CAS  PubMed  Google Scholar 

  • Aguilar RC, Wendland B (2003) Ubiquitin: not just for proteasomes anymore. Curr Opin Cell Biol 15:184–190

    Article  CAS  PubMed  Google Scholar 

  • Bae YJ, Park KS, Kang SJ (2003) Genomic organization and expression of parkin in Drosophila melanogaster. Exp Mol Med 35:393–402

    CAS  PubMed  Google Scholar 

  • Beites CL, Xie H, Bowser R, Trimble WS (1999) The septin CDCrel-1 binds syntaxin and inhibits exocytosis. Nat Neurosci 2:434–439

    Article  CAS  PubMed  Google Scholar 

  • Berke SJ, Paulson HL (2003) Protein aggregation and the ubiquitin proteasome pathway: gaining the UPPer hand on neurodegeneration. Curr Opin Genet Dev 13:253–261

    Article  CAS  PubMed  Google Scholar 

  • Braak H, Del Tredici K, Rub U, Vos RA de, Jansen Steur EN, Braak E (2003) Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging 24:197–211

    Article  PubMed  Google Scholar 

  • Choi P, Snyder H, Petrucelli L, Theisler C, Chong M, Zhang Y, Lim K, Chung KK, Kehoe K, D’Adamio L, Lee JM, Cochran E, Bowser R, Dawson TM, Wolozin B (2003) SEPT5_v2 is a parkin-binding protein. Brain Res Mol Brain Res 117:179–189

    Article  CAS  PubMed  Google Scholar 

  • Chung KK, Zhang Y, Lim KL, Tanaka Y, Huang H, Gao J, Ross CA, Dawson VL, Dawson TM (2001) Parkin ubiquitinates the alpha-synuclein-interacting protein, synphilin-1: implications for Lewy-body formation in Parkinson disease. Nat Med 7:1144–1150

    Article  CAS  PubMed  Google Scholar 

  • Chung KK, Thomas B, Li X, Pletnikova O, Troncoso JC, Marsh L, Dawson VL, Dawson TM (2004) S-Nitrosylation of parkin regulates ubiquitination and compromises parkins protective function. Science 304:1328–1330

    Article  CAS  PubMed  Google Scholar 

  • Ciechanover A, Brundin P (2003) The ubiquitin proteasome system in neurodegenerative diseases: sometimes the chicken, sometimes the egg. Neuron 40:427–446

    Article  CAS  PubMed  Google Scholar 

  • Corti O, Hampe C, Koutnikova H, Darios F, Jacquier S, Prigent A, Robinson JC, Pradier L, Ruberg M, Mirande M, Hirsch E, Rooney T, Fournier A, Brice A (2003) The p38 subunit of the aminoacyl-tRNA synthetase complex is a parkin substrate: linking protein biosynthesis and neurodegeneration. Hum Mol Genet 12:1427–1437

    Article  CAS  PubMed  Google Scholar 

  • Culetto E, Sattelle DB (2000) A role for Caenorhabditis elegans in understanding the function and interactions of human disease genes. Hum Mol Genet 9:869–877

    Article  CAS  PubMed  Google Scholar 

  • Dawson TM, Dawson VL (2003a) Molecular pathways of neurodegeneration in Parkinson’s disease. Science 302:819–822

    Article  CAS  PubMed  Google Scholar 

  • Dawson TM, Dawson VL (2003b) Rare genetic mutations shed light on the pathogenesis of Parkinson disease. J Clin Invest 111:145–151

    Article  CAS  PubMed  Google Scholar 

  • Dong Z, Ferger B, Paterna JC, Vogel D, Furler S, Osinde M, Feldon J, Bueler H (2003) Dopamine-dependent neurodegeneration in rats induced by viral vector-mediated overexpression of the parkin target protein, CDCrel-1. Proc Natl Acad Sci USA 100:12438–12443

    Article  CAS  PubMed  Google Scholar 

  • Engelender S, Kaminsky Z, Guo X, Sharp AH, Amaravi RK, Kleiderlein JJ, Margolis RL, Troncoso JC, Lanahan AA, Worley PF, Dawson VL, Dawson TM, Ross CA (1999) Synphilin-1 associates with alpha-synuclein and promotes the formation of cytosolic inclusions. Nat Genet 22:110–114

    Article  CAS  PubMed  Google Scholar 

  • Farrer M, Chan P, Chen R, Tan L, Lincoln S, Hernandez D, Forno L, Gwinn-Hardy K, Petrucelli L, Hussey J, Singleton A, Tanner C, Hardy J, Langston JW (2001) Lewy bodies and parkinsonism in families with parkin mutations. Ann Neurol 50:293–300

    Article  CAS  PubMed  Google Scholar 

  • Feany MB, Bender WW (2000) A Drosophila model of Parkinson’s disease. Nature 404:394–398

    Article  CAS  PubMed  Google Scholar 

  • Feany MB, Pallanck LJ (2003) Parkin: a multipurpose neuroprotective agent? Neuron 38:13–16

    Article  CAS  PubMed  Google Scholar 

  • Giasson BI, Lee VM (2001) Parkin and the molecular pathways of Parkinson’s disease. Neuron 31:885–888

    Article  CAS  PubMed  Google Scholar 

  • Giasson BI, Lee VM (2003) Are ubiquitination pathways central to Parkinson’s disease? Cell 114:1–8

    Article  CAS  PubMed  Google Scholar 

  • Goedert M (2001) Alpha-synuclein and neurodegenerative diseases. Nat Rev Neurosci 2:492–501

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Gomez-Tortosa E, Newell K, Irizarry MC, Sanders JL, Hyman BT (2000) Alpha-synuclein immunoreactivity in dementia with Lewy bodies: morphological staging and comparison with ubiquitin immunostaining. Acta Neuropathol (Berl) 99:352–357

    Article  CAS  Google Scholar 

  • Gouider-Khouja N, Larnaout A, Amouri R, Sfar S, Belal S, Ben Hamida C, Ben Hamida M, Hattori N, Mizuno Y, Hentati F (2003) Autosomal recessive parkinsonism linked to parkin gene in a Tunisian family. Clinical, genetic and pathological study. Parkinsonism Relat Disord 9:247–251

    Article  PubMed  Google Scholar 

  • 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 100:4078–4083

    Article  CAS  PubMed  Google Scholar 

  • Hayashi S, Wakabayashi K, Ishikawa A, Nagai H, Saito M, Maruyama M, Takahashi T, Ozawa T, Tsuji S, Takahashi H (2000) An autopsy case of autosomal-recessive juvenile parkinsonism with a homozygous exon 4 deletion in the parkin gene. Mov Disord 15:884–888

    Article  CAS  PubMed  Google Scholar 

  • Horowitz JM, Myers J, Stachowiak MK, Torres G (1999) Identification and distribution of parkin in rat brain. Neuroreport 10:3393–3397

    CAS  PubMed  Google Scholar 

  • Huynh DP, Scoles DR, Nguyen D, Pulst SM (2003) The autosomal recessive juvenile Parkinson disease gene product, parkin, interacts with and ubiquitinates synaptotagmin XI. Hum Mol Genet 12:2587–2597

    Article  CAS  PubMed  Google Scholar 

  • Imai Y, Soda M, Takahashi R (2000) Parkin suppresses unfolded protein stress-induced cell death through its E3 ubiquitin-protein ligase activity. J Biol Chem 275:35661–35664

    Article  CAS  PubMed  Google Scholar 

  • Imai Y, Soda M, Inoue H, Hattori N, Mizuno Y, Takahashi R (2001) An unfolded putative transmembrane polypeptide, which can lead to endoplasmic reticulum stress, is a substrate of parkin. Cell 105:891–902

    Article  CAS  PubMed  Google Scholar 

  • Imai Y, Soda M, Hatakeyama S, Akagi T, Hashikawa T, Nakayama KI, Takahashi R (2002) CHIP is associated with parkin, a gene responsible for familial Parkinson’s disease, and enhances its ubiquitin ligase activity. Mol Cell 10:55–67

    Article  CAS  PubMed  Google Scholar 

  • Ishikawa A, Tsuji S (1996) Clinical analysis of 17 patients in 12 Japanese families with autosomal-recessive type juvenile parkinsonism. Neurology 47:160–166

    CAS  PubMed  Google Scholar 

  • Itier JM, Ibanez P, Mena MA, Abbas N, Cohen-Salmon C, Bohme GA, Laville M, et al (2003) Parkin gene inactivation alters behaviour and dopamine neurotransmission in the mouse. Hum Mol Genet 12:2277–2291

    Article  CAS  PubMed  Google Scholar 

  • Kann M, Jacobs H, Mohrmann K, Schumacher K, Hedrich K, Garrels J, Wiegers K, Schwinger E, Pramstaller PP, Breakefield XO, Ozelius LJ, Vieregge P, Klein C (2002) Role of parkin mutations in 111 community-based patients with early-onset parkinsonism. Ann Neurol 51:621–625

    Article  CAS  PubMed  Google Scholar 

  • 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 392:605–608

    Article  CAS  PubMed  Google Scholar 

  • Kitada T, Asakawa S, Minoshima S, Mizuno Y, Shimizu N (2000) Molecular cloning, gene expression, and identification of a splicing variant of the mouse parkin gene. Mamm Genome 11:417–421

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Lang AE, Lozano AM (1998) Parkinson’s disease. First of two parts. N Engl J Med 339:1044–1053

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Marx FP, Holzmann C, Strauss KM, Li L, Eberhardt O, Gerhardt E, Cookson MR, Hernandez D, Farrer MJ, Kachergus J, Engelender S, Ross CA, Berger K, Schols L, Schulz JB, Riess O, Kruger R (2003) Identification and functional characterization of a novel R621C mutation in the synphilin-1 gene in Parkinson’s disease. Hum Mol Genet 12:1223–1231

    Article  CAS  PubMed  Google Scholar 

  • Mata IF, Lockhart PJ, Farrer MJ (2004) Parkin genetics: one model for Parkinson’s disease. Hum Mol Genet 13 (Suppl 1):R127–R133

    Article  CAS  PubMed  Google Scholar 

  • Matsumine H, Saito M, Shimoda-Matsubayashi S, Tanaka H, Ishikawa A, Nakagawa-Hattori Y, Yokochi M, Kobayashi T, Igarashi S, Takano H, Sanpei K, Koike R, Mori H, Kondo T, Mizutani Y, Schaffer AA, Yamamura Y, Nakamura S, Kuzuhara S, Tsuji S, Mizuno Y (1997) Localization of a gene for an autosomal recessive form of juvenile parkinsonism to chromosome 6q25.2–27. Am J Hum Genet 60:588–596

    CAS  PubMed  Google Scholar 

  • Moore DJ, Dawson VL, Dawson TM (2003) Role for the ubiquitin–proteasome system in Parkinson’s disease and other neurodegenerative brain amyloidoses. Neuromol Med 4:95–108

    Article  Google Scholar 

  • Mori H, Kondo T, Yokochi M, Matsumine H, Nakagawa-Hattori Y, Miyake T, Suda K, Mizuno Y (1998) Pathologic and biochemical studies of juvenile parkinsonism linked to chromosome 6q. Neurology 51:890–892

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Pawlyk AC, Giasson BI, Sampathu DM, Perez FA, Lim KL, Dawson VL, Dawson TM, Palmiter RD, Trojanowski JQ, Lee VM (2003) Novel monoclonal antibodies demonstrate biochemical variation of brain parkin with age. J Biol Chem 278:48120–48128

    Article  CAS  PubMed  Google Scholar 

  • Peng XR, Jia Z, Zhang Y, Ware J, Trimble WS (2002) The septin CDCrel-1 is dispensable for normal development and neurotransmitter release. Mol Cell Biol 22:378–387

    Article  CAS  PubMed  Google Scholar 

  • Petrucelli L, O’Farrell C, Lockhart PJ, Baptista M, Kehoe K, Vink L, Choi P, Wolozin B, Farrer M, Hardy J, Cookson MR (2002) Parkin protects against the toxicity associated with mutant alpha-synuclein: proteasome dysfunction selectively affects catecholaminergic neurons. Neuron 36:1007–1019

    Article  CAS  PubMed  Google Scholar 

  • Pickart CM (2001) Mechanisms underlying ubiquitination. Annu Rev Biochem 70:503–533

    Article  CAS  PubMed  Google Scholar 

  • Pickart CM (2004) Back to the future with ubiquitin. Cell 116:181–190

    Article  CAS  PubMed  Google Scholar 

  • Ren Y, Zhao J, Feng J (2003) Parkin binds to alpha/beta tubulin and increases their ubiquitination and degradation. J Neurosci 23:3316–3324

    CAS  PubMed  Google Scholar 

  • Sampathu DM, Giasson BI, Pawlyk AC, Trojanowski JQ, Lee VM (2003) Ubiquitination of alpha-synuclein is not required for formation of pathological inclusions in alpha-synucleinopathies. Am J Pathol 163:91–100

    CAS  PubMed  Google Scholar 

  • Schubert U, Anton LC, Gibbs J, Norbury CC, Yewdell JW, Bennink JR (2000) Rapid degradation of a large fraction of newly synthesized proteins by proteasomes. Nature 404:770–774

    Article  CAS  PubMed  Google Scholar 

  • Shimura H, Hattori N, Kubo S, Yoshikawa M, Kitada T, Matsumine H, Asakawa S, Minoshima S, Yamamura Y, Shimizu N, Mizuno Y (1999) Immunohistochemical and subcellular localization of parkin protein: absence of protein in autosomal recessive juvenile parkinsonism patients. Ann Neurol 45:668–672

    Article  CAS  PubMed  Google Scholar 

  • 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 25:302–305

    Article  CAS  PubMed  Google Scholar 

  • Shimura H, Schlossmacher MG, Hattori N, Frosch MP, Trockenbacher A, Schneider R, Mizuno Y, Kosik KS, Selkoe DJ (2001) Ubiquitination of a new form of alpha-synuclein by parkin from human brain: implications for Parkinson’s disease. Science 293:263–269

    Article  CAS  PubMed  Google Scholar 

  • Spillantini MG, Crowther RA, Jakes R, Cairns NJ, Lantos PL, Goedert M (1998a) Filamentous alpha-synuclein inclusions link multiple system atrophy with Parkinson’s disease and dementia with Lewy bodies. Neurosci Lett 251:205–208

    Article  CAS  PubMed  Google Scholar 

  • Spillantini MG, Crowther RA, Jakes R, Hasegawa M, Goedert M (1998b) Alpha-synuclein in filamentous inclusions of Lewy bodies from Parkinson’s disease and dementia with Lewy bodies. Proc Natl Acad Sci USA 95:6469–6473

    Article  CAS  PubMed  Google Scholar 

  • Staropoli JF, McDermott C, Martinat C, Schulman B, Demireva E, Abeliovich A (2003) Parkin is a component of an SCF-like ubiquitin ligase complex and protects postmitotic neurons from kainate excitotoxicity. Neuron 37:735–749

    Article  CAS  PubMed  Google Scholar 

  • Takahashi H, Ohama E, Suzuki S, Horikawa Y, Ishikawa A, Morita T, Tsuji S, Ikuta F (1994) Familial juvenile parkinsonism: clinical and pathologic study in a family. Neurology 44:437–441

    CAS  PubMed  Google Scholar 

  • Tanaka K, Suzuki T, Chiba T, Shimura H, Hattori N, Mizuno Y (2001) Parkin is linked to the ubiquitin pathway. J Mol Med 79:482–494

    Article  CAS  PubMed  Google Scholar 

  • Tyers M, Jorgensen P (2000) Proteolysis and the cell cycle: with this RING I do thee destroy. Curr Opin Genet Dev 10:54–64

    Article  CAS  PubMed  Google Scholar 

  • von Coelln R, Thomas B, Savitt JM, Lim KL, Sasaki M, Hess EJ, Dawson VL, Dawson TM (2004) Loss of locus coeruleus neurons and reduced startle in parkin null mice. Proc Natl Acad Sci USA 101:10744–10749

    Article  PubMed  Google Scholar 

  • Wakabayashi K, Engelender S, Yoshimoto M, Tsuji S, Ross CA, Takahashi H (2000) Synphilin-1 is present in Lewy bodies in Parkinson’s disease. Ann Neurol 47:521–523

    Article  CAS  PubMed  Google Scholar 

  • Wakabayashi K, Engelender S, Tanaka Y, Yoshimoto M, Mori F, Tsuji S, Ross CA, Takahashi H (2002) Immunocytochemical localization of synphilin-1, an alpha-synuclein-associated protein, in neurodegenerative disorders. Acta Neuropathol (Berl) 103:209–214

    Article  CAS  Google Scholar 

  • Warrenburg BP van de, Lammens M, Lucking CB, Denefle P, Wesseling P, Booij J, Praamstra P, Quinn N, Brice A, Horstink MW (2001) Clinical and pathologic abnormalities in a family with parkinsonism and parkin gene mutations. Neurology 56:555–557

    PubMed  Google Scholar 

  • West A, Farrer M, Petrucelli L, Cookson M, Lockhart P, Hardy J (2001) Identification and characterization of the human parkin gene promoter. J Neurochem 78:1146–1152

    Article  CAS  PubMed  Google Scholar 

  • West A, Periquet M, Lincoln S, Lucking CB, Nicholl D, Bonifati V, Rawal N, Gasser T, Lohmann E, Deleuze JF, Maraganore D, Levey A, Wood N, Durr A, Hardy J, Brice A, Farrer M (2002) Complex relationship between parkin mutations and Parkinson disease. Am J Med Genet 114:584–591

    Article  PubMed  Google Scholar 

  • 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 326:11–19

    Article  CAS  PubMed  Google Scholar 

  • Yamamura Y, Sobue I, Ando K, Iida M, Yanagi T (1973) Paralysis agitans of early onset with marked diurnal fluctuation of symptoms. Neurology 23:239–244

    CAS  PubMed  Google Scholar 

  • Yamamura Y, Arihiro K, Kohriyama T, Nakamura S (1993) Early-onset parkinsonism with diurnal fluctuation—clinical and pathological studies. Rinsho Shinkeigaku 33:491–496

    CAS  PubMed  Google Scholar 

  • Yang Y, Nishimura I, Imai Y, Takahashi R, Lu B (2003) Parkin suppresses dopaminergic neuron-selective neurotoxicity induced by Pael-R in Drosophila. Neuron 37:911–924

    Article  CAS  PubMed  Google Scholar 

  • Zhang Y, Dawson VL, Dawson TM (2000a) Oxidative stress and genetics in the pathogenesis of Parkinson’s disease. Neurobiol Dis 7:240–250

    Article  CAS  PubMed  Google Scholar 

  • Zhang Y, Gao J, Chung KK, Huang H, Dawson VL, Dawson TM (2000b) 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 97:13354–13359

    Article  CAS  PubMed  Google Scholar 

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von Coelln, R., Dawson, V.L. & Dawson, T.M. Parkin-associated Parkinson’s disease. Cell Tissue Res 318, 175–184 (2004). https://doi.org/10.1007/s00441-004-0924-4

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