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Recent advances in Parkinson’s disease genetics

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Abstract

The last 5 years have seen rapid progress in Parkinson’s disease (PD) genetics, with the publication of a series of large-scale genome wide association studies for PD, and evaluation of the roles of the LRRK2 and GBA genes in the aetiology of PD. We are beginning to develop a coherent picture of the interplay of Mendelian and non-Mendelian factors in PD. Pathways involved in mitochondrial quality control (mitophagy), lysosomal function and immune function are emerging as important in the pathogenesis of PD. These pathways represent a target for therapeutic intervention and a way in which the heterogeneity of disease cause, as well as disease mechanism, can be established. In the future, there is likely to be an individualised basis for the treatment of PD, linked to the identification of specific genetic factors.

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References

  1. Lees AJ, Hardy J, Revesz T (2009) Parkinson’s disease. Lancet 373(9680):2055–2066

    Article  CAS  PubMed  Google Scholar 

  2. Goedert M, Spillantini MG, Del Tredici K, Braak H (2013) 100 years of Lewy pathology. Nat Rev Neurol 9(1):13–24

    Article  CAS  PubMed  Google Scholar 

  3. Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, Dutra A et al (1997) Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science 276(5321):2045–2047 (New York, N.Y.)

    Article  CAS  PubMed  Google Scholar 

  4. Krüger R, Kuhn W, Müller T, Woitalla D, Graeber M, Kösel S et al (1998) Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson’s disease. Nat Genet 18(2):106–108

    Article  PubMed  Google Scholar 

  5. Zarranz JJ, Alegre J, Gómez-Esteban JC, Lezcano E, Ros R, Ampuero I et al (2004) The new mutation, E46 K, of alpha-synuclein causes Parkinson and Lewy body dementia. Ann Neurol 55(2):164–173

    Article  CAS  PubMed  Google Scholar 

  6. Singleton AB, Farrer M, Johnson J, Singleton A, Hague S, Kachergus J et al (2003) Alpha-Synuclein locus triplication causes Parkinson’s disease. Science 302(5646):841 (New York, N.Y.)

    Article  CAS  PubMed  Google Scholar 

  7. Conway KA (2000) Acceleration of oligomerization, not fibrillization, is a shared property of both alpha -synuclein mutations linked to early-onset Parkinson’s disease: implications for pathogenesis and therapy. Proc Natl Acad Sci 97(2):571–576

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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

  9. Proukakis C, Dudzik CG, Brier T, MacKay DS, Cooper JM, Millhauser GL, Houlden H, Schapira AH (2013) A novel α-synuclein missense mutation in Parkinson disease. Neurology 80(11):1062–1064. doi:10.1212/WNL.0b013e31828727ba

    Article  PubMed Central  PubMed  Google Scholar 

  10. Kiely AP, Asi YT, Kara E, Limousin P, Ling H, Lewis P, Proukakis C, Quinn N, Lees AJ, Hardy J, Revesz T, Houlden H, Holton JL (2013) α-Synucleinopathy associated with G51D SNCA mutation: a link between Parkinson’s disease and multiple system atrophy? Acta Neuropathol 125(5):753–769. doi:10.1007/s00401-013-1096-7

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Lesage S, Anheim M, Letournel F, Bousset L, Honoré A, Rozas N, Pieri L, Madiona K, Dürr A, Melki R, Verny C, Brice A; for the French Parkinson's Disease Genetics (PDG) Study Group (2013) G51D α-synuclein mutation causes a novel parkinsonian-pyramidal syndrome. Ann Neurol. doi:10.1002/ana.23894

  12. Gwinn-Hardy K, Mehta ND, Farrer M, Maraganore D, Muenter M, Yen SH et al (2000) Distinctive neuropathology revealed by alpha-synuclein antibodies in hereditary parkinsonism and dementia linked to chromosome 4p. Acta Neuropathol 99(6):663–672

    Article  CAS  PubMed  Google Scholar 

  13. Healy DG, Falchi M, O’Sullivan SS, Bonifati V, Durr A, Bressman S et al (2008) Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson’s disease: a case-control study. Lancet Neurol 7(7):583–590

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. Hassin-Baer S, Laitman Y, Azizi E, Molchadski I, Galore-Haskel G, Barak F et al (2009) The leucine rich repeat kinase 2 (LRRK2) G2019S substitution mutation. Association with Parkinson disease, malignant melanoma and prevalence in ethnic groups in Israel. J Neurol 256(3):483–487

    Article  CAS  PubMed  Google Scholar 

  15. Lesage S, Dürr A, Tazir M, Lohmann E, Leutenegger A-L, Janin S et al (2006) LRRK2 G2019S as a cause of Parkinson’s disease in North African Arabs. N Engl J Med 354(4):422–423

    Article  CAS  PubMed  Google Scholar 

  16. Ozelius LJ, Senthil G, Saunders-Pullman R, Ohmann E, Deligtisch A, Tagliati M et al (2006) LRRK2 G2019S as a cause of Parkinson’s disease in Ashkenazi Jews. N Engl J Med 354(4):424–425

    Article  CAS  PubMed  Google Scholar 

  17. Paisán-Ruíz C, Jain S, Evans EW, Gilks WP, Simón J, Van der Brug M et al (2004) Cloning of the gene containing mutations that cause PARK8-linked Parkinson’s disease. Neuron 44(4):595–600

    Article  PubMed  Google Scholar 

  18. Zimprich A, Biskup S, Leitner P, Lichtner P, Farrer M, Lincoln S et al (2004) Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron 44(4):601–607

    Article  CAS  PubMed  Google Scholar 

  19. Latourelle JC, Sun M, Lew MF, Suchowersky O, Klein C, Golbe LI et al (2008) The Gly2019Ser mutation in LRRK2 is not fully penetrant in familial Parkinson’s disease: the GenePD study. BMC Med 6:32

    Article  PubMed Central  PubMed  Google Scholar 

  20. Cookson MR (2010) The role of leucine-rich repeat kinase 2 (LRRK2) in Parkinson’s disease. Nat Rev Neurosci 11(12):791–797. doi:10.1038/nrn2935

    Google Scholar 

  21. Lewis PA, Manzoni C (2012) LRRK2 and human disease: a complicated question or a question of complexes? Sci Signal 5(207):pe2. doi:10.1126/scisignal.2002680

    Article  PubMed  Google Scholar 

  22. Lewis PA (2009) The function of ROCO proteins in health and disease. Biol Cell/Under Auspices Eur Cell Biol Organ 101(3):183–191

    Article  CAS  Google Scholar 

  23. Plun-Favreau H, Lewis PA, Hardy J, Martins LM, Wood NW (2010) Cancer and neurodegeneration: between the devil and the deep blue sea. PLoS Genet 6(12):e1001257. doi:10.1371/journal.pgen.1001257

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. Bajaj A, Driver JA, Schernhammer ES (2010) Parkinson’s disease and cancer risk: a systematic review and meta-analysis. Cancer Causes Control: CCC 21(5):697–707

    Article  PubMed  Google Scholar 

  25. Morris LGT, Veeriah S, Chan TA (2010) Genetic determinants at the interface of cancer and neurodegenerative disease. Oncogene 29(24):3453–3464

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. Saunders-Pullman R, Barrett MJ, Stanley KM, Luciano MS, Shanker V, Severt L et al (2010) LRRK2 G2019S mutations are associated with an increased cancer risk in Parkinson disease. Mov Disord: Off J Mov Disord Soc 25(15):2536–2541

    Article  Google Scholar 

  27. Vilariño-Güell C, Wider C, Ross OA, Dachsel JC, Kachergus JM, Lincoln SJ et al (2011) VPS35 mutations in Parkinson disease. Am J Hum Genet 89(1):162–167

    Article  PubMed Central  PubMed  Google Scholar 

  28. Lesage S, Condroyer C, Klebe S, Honoré A, Tison F, Brefel-Courbon C, Dürr A, Brice A; French Parkinson’s Disease Genetics Study Group (2012) Identification of VPS35 mutations replicated in French families with Parkinson disease. Neurology 78(18):1449–1450. doi:10.1212/WNL.0b013e318253d5f2

    Google Scholar 

  29. Sharma M, Ioannidis JP a, Aasly JO, Annesi G, Brice A, Bertram L et al (2012) A multi-centre clinico-genetic analysis of the VPS35 gene in Parkinson disease indicates reduced penetrance for disease-associated variants. J Med Genet 49(11):721–726

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  30. Sheerin U-M, Charlesworth G, Bras J, Guerreiro R, Bhatia K, Foltynie T et al (2012) Screening for VPS35 mutations in Parkinson’s disease. Neurobiol Aging 33(4):838.e1–838.e5

    Article  CAS  Google Scholar 

  31. Ando M, Funayama M, Li Y, Kashihara K, Murakami Y, Ishizu N et al (2012) VPS35 mutation in Japanese patients with typical Parkinson’s disease. Mov Disord: Off J Mov Disord Soc 27(11):1413–1417

    Article  CAS  Google Scholar 

  32. Chartier-Harlin M-C, Dachsel JC, Vilariño-Güell C, Lincoln SJ, Leprêtre F, Hulihan MM et al (2011) Translation initiator EIF4G1 mutations in familial Parkinson disease. Am J Hum Genet 89(3):398–406

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. Tucci A, Charlesworth G, Sheerin U-M, Plagnol V, Wood NW, Hardy J (2012) Study of the genetic variability in a Parkinson’s disease gene: EIF4G1. Neurosci Lett 518(1):19–22

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  34. Nuytemans K, Bademci G, Inchausti V, Dressen A, Kinnamon DD, Mehta A et al (2013) Whole exome sequencing of rare variants in EIF4G1 and VPS35 in Parkinson disease. Neurology 80(11):982–989

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  35. Lesage S, Condroyer C, Klebe S, Lohmann E, Durif F, Damier P et al (2012) EIF4G1 in familial Parkinson’s disease: pathogenic mutations or rare benign variants? Neurobiol Aging 33(9):2233.e1–2233.e5

    Article  CAS  Google Scholar 

  36. Schulte EC, Mollenhauer B, Zimprich A, Bereznai B, Lichtner P, Haubenberger D et al (2012) Variants in eukaryotic translation initiation factor 4G1 in sporadic Parkinson’s disease. Neurogenetics 13(3):281–285

    Article  CAS  PubMed  Google Scholar 

  37. Kitada T, Askawa S, Hattori N, Matsumine H, Yokochi M, Mizuno Y et al (1998) Mutations in the parkin gene cause autosomal recessive juvenile Parkinsonism. Nature 392:605–608

    Article  CAS  PubMed  Google Scholar 

  38. Kilarski LL, Pearson JP, Newsway V, Majounie E, Knipe MDW, Misbahuddin A et al (2012) Systematic Review and UK-Based Study of PARK2 (parkin), PINK1, PARK7 (DJ-1) and LRRK2 in early-onset Parkinson’s disease. Mov Disord 27(12):1522–1529

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  40. Shimura H, Hattori N, Kubo S i, Mizuno Y, Asakawa S, Minoshima S et al (2000) Familial Parkinson disease gene product, parkin, is a ubiquitin-protein ligase. Nat Genet 25(3):302–305

    Article  CAS  PubMed  Google Scholar 

  41. Valente EM, Abou-Sleiman PM, Caputo V, Muqit MMK, Harvey K, Gispert S et al (2004) Hereditary early-onset Parkinson’s disease caused by mutations in PINK1. Science 304(5674):1158–1160 (New York, N.Y.)

    Article  CAS  PubMed  Google Scholar 

  42. Schon E a, Przedborski S (2011) Mitochondria: the next (neurode) generation. Neuron 70(6):1033–1053

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  43. Kuroda Y, Mitsui T, Kunishige M, Shono M, Akaike M, Azuma H et al (2006) Parkin enhances mitochondrial biogenesis in proliferating cells. Hum Mol Genet 15(6):883–895

    Article  CAS  PubMed  Google Scholar 

  44. Shin J-H, Ko HS, Kang H, Lee Y, Lee Y-I, Pletinkova O et al (2011) PARIS (ZNF746) repression of PGC-1α contributes to neurodegeneration in Parkinson’s disease. Cell 144(5):689–702

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  45. Clark IE, Dodson MW, Jiang C, Cao JH, Huh JR, Seol JH et al (2006) Drosophila pink1 is required for mitochondrial function and interacts genetically with parkin. Nature 441(7097):1162–1166

    Article  CAS  PubMed  Google Scholar 

  46. Park J, Lee SB, Lee S, Kim Y, Song S, Kim S et al (2006) Mitochondrial dysfunction in Drosophila PINK1 mutants is complemented by parkin. Nature 441(7097):1157–1161

    Article  CAS  PubMed  Google Scholar 

  47. Gandhi S, Wood-Kaczmar A, Yao Z, Plun-Favreau H, Deas E, Klupsch K et al (2009) PINK1-associated Parkinson’s disease is caused by neuronal vulnerability to calcium-induced cell death. Mol Cell 33(5):627–638

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  48. Bonifati V, Rizzu P, Van Baren MJ, Schaap O, Breedveld GJ, Krieger E et al (2003) Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism. Science 299(5604):256–259 (New York, N.Y.)

    Article  CAS  PubMed  Google Scholar 

  49. Canet-Avilés RM, Wilson MA, Miller DW, Ahmad R, McLendon C, Bandyopadhyay S et al (2004) The Parkinson’s disease protein DJ-1 is neuroprotective due to cysteine-sulfinic acid-driven mitochondrial localization. Proc Natl Acad Sci USA 101(24):9103–9108

    Article  PubMed Central  PubMed  Google Scholar 

  50. Miyakawa S, Ogino M, Funabe S, Uchino A, Shimo Y, Hattori N et al (2013) Lewy body pathology in a patient with a homozygous Parkin deletion. Mov Disord: Off J Mov Disord Soc 28(3):388–391

    Article  Google Scholar 

  51. Doherty KM, Silveira-Moriyama L, Parkkinen L, Healy DG, Farrell M, Mencacci NE et al (2013) Parkin disease: A clinicopathologic entity? JAMA Neurol 4:1–9

    Google Scholar 

  52. Ahlskog JE (2009) Parkin and PINK1 parkinsonism may represent nigral mitochondrial cytopathies distinct from Lewy body Parkinson’s disease. Parkinsonism Relat Disord 15(10):721–727

    Article  PubMed Central  PubMed  Google Scholar 

  53. Ramirez A, Heimbach A, Gründemann J, Stiller B, Hampshire D, Cid LP et al (2006) Hereditary parkinsonism with dementia is caused by mutations in ATP13A2, encoding a lysosomal type 5 P-type ATPase. Nat Genet 38(10):1184–1191

    Article  CAS  PubMed  Google Scholar 

  54. Usenovic M, Tresse E, Mazzulli JR, Taylor JP, Krainc D (2012) Deficiency of ATP13A2 leads to lysosomal dysfunction, α-synuclein accumulation, and neurotoxicity. J Neurosci: Off J Soc Neurosci 32(12):4240–4246

    Article  CAS  Google Scholar 

  55. Paisán-Ruiz C, Guevara R, Federoff M, Hanagasi H, Sina F, Elahi E et al (2010) Early-onset L-dopa-responsive parkinsonism with pyramidal signs due to ATP13A2, PLA2G6, FBXO7 and spatacsin mutations. Mov Disord: Off J Mov Disord Soc 25(12):1791–1800

    Article  Google Scholar 

  56. Paisan-Ruiz C, Bhatia KP, Li A, Hernandez D, Davis M, Wood NW et al (2009) Characterization of PLA2G6 as a locus for dystonia-parkinsonism. Ann Neurol 65(1):19–23

    Article  PubMed  Google Scholar 

  57. Kauther KM, Höft C, Rissling I, Oertel WH, Möller JC (2011) The PLA2G6 gene in early-onset Parkinson’s disease. Mov Disord: Off J Mov Disord Soc 26(13):2415–2417

    Article  Google Scholar 

  58. Di Fonzo A, Dekker MCJ, Montagna P, Baruzzi A, Yonova EH (2009) Correia Guedes L, et al. FBXO7 mutations cause autosomal recessive, early-onset parkinsonian-pyramidal syndrome. Neurology 72(3):240–245

    Article  PubMed  Google Scholar 

  59. Deng H, Liang H, Jankovic J (2012) F-Box Only Protein 7 Gene in Parkinsonian-Pyramidal Disease. Archives Neurol 1:1–5

    Google Scholar 

  60. Simón-Sánchez J, Kilarski LL, Nalls MA, Martinez M, Schulte C, Holmans P et al (2012) Cooperative genome-wide analysis shows increased homozygosity in early onset Parkinson’s disease. PLoS ONE 7(3):e28787

    Article  PubMed Central  PubMed  Google Scholar 

  61. Simón-Sánchez J, Schulte C, Bras JM, Sharma M, Gibbs JR, Berg D et al (2009) Genome-wide association study reveals genetic risk underlying Parkinson’s disease. Nat Genet 41(12):1308–1312

    Article  PubMed Central  PubMed  Google Scholar 

  62. Satake W, Nakabayashi Y, Mizuta I, Hirota Y, Ito C, Kubo M et al (2009) Genome-wide association study identifies common variants at four loci as genetic risk factors for Parkinson’s disease. Nat Genet 41(12):1303–1307

    Article  CAS  PubMed  Google Scholar 

  63. Pankratz N, Beecham GW, DeStefano AL, Dawson TM, Doheny KF, Factor SA et al (2012) Meta-analysis of Parkinson’s disease: identification of a novel locus, RIT2. Ann Neurol 71(3):370–384

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  64. Pankratz N, Wilk JB, Latourelle JC, DeStefano AL, Halter C, Pugh EW et al (2009) Genomewide association study for susceptibility genes contributing to familial Parkinson disease. Hum Genet 124(6):593–605

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  65. Edwards TL, Scott WK, Almonte C, Burt A, Powell EH, Beecham GW et al (2010) Genome-wide association study confirms SNPs in SNCA and the MAPT region as common risk factors for Parkinson disease. Ann Hum Genet 74(2):97–109

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  66. Hamza TH, Zabetian CP, Tenesa A, Laederach A, Montimurro J, Yearout D et al (2010) Common genetic variation in the HLA region is associated with late-onset sporadic Parkinson’s disease. Nat Genet 42(9):781–785

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  67. Saad M, Lesage S, Saint-Pierre A, Corvol J-C, Zelenika D, Lambert J-C et al (2011) Genome-wide association study confirms BST1 and suggests a locus on 12q24 as the risk loci for Parkinson’s disease in the European population. Hum Mol Genet 20(3):615–627

    Article  PubMed  Google Scholar 

  68. Spencer CCA, Plagnol V, Strange A, Gardner M, Paisan-Ruiz C, Band G et al (2011) Dissection of the genetics of Parkinson’s disease identifies an additional association 5’ of SNCA and multiple associated haplotypes at 17q21. Hum Mol Genet 20(2):345–353

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  69. Nalls MA, Plagnol V, Hernandez DG, Sharma M, Sheerin U-M, Saad M et al (2011) Imputation of sequence variants for identification of genetic risks for Parkinson’s disease: a meta-analysis of genome-wide association studies. Lancet 377(9766):641–649

    Article  PubMed  Google Scholar 

  70. Plagnol V, Nalls MA, Bras JM, Hernandez DG, Sharma M, Sheerin U-M et al (2011) A two-stage meta-analysis identifies several new loci for Parkinson’s disease. PLoS Genet 7(6):e1002142

    Article  CAS  Google Scholar 

  71. Do CB, Tung JY, Dorfman E, Kiefer AK, Drabant EM, Francke U et al (2011) Web-based genome-wide association study identifies two novel loci and a substantial genetic component for Parkinson’s disease. PLoS Genet 7(6):e1002141

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  72. Liu X, Cheng R, Verbitsky M, Kisselev S, Browne A, Mejia-Sanatana H et al (2011) Genome-wide association study identifies candidate genes for Parkinson’s disease in an Ashkenazi Jewish population. BMC Med Genet 12:104

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  73. Pihlstrøm L, Axelsson G, Bjørnarå KA, Dizdar N, Fardell C, Forsgren L et al (2012) Supportive evidence for 11 loci from genome-wide association studies in Parkinson’s disease. Neurobiol Aging 34(6):1708.e7–1708.e13

    Article  Google Scholar 

  74. Sharma M, Ioannidis JPA, Aasly JO, Annesi G, Brice A, Van Broeckhoven C et al (2012) Large-scale replication and heterogeneity in Parkinson disease genetic loci. Neurology 79(7):659–667

    Article  PubMed Central  PubMed  Google Scholar 

  75. Hardy J, Singleton A (2009) Genomewide association studies and human disease. N Engl J Med 360(17):1759–1768

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  76. Birney E, Stamatoyannopoulos JA, Dutta A, Guigó R, Gingeras TR, Margulies EH et al (2007) Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project. Nature 447(7146):799–816

    Article  CAS  PubMed  Google Scholar 

  77. Keller MF, Saad M, Bras J, Bettella F, Nicolaou N, Simón-Sánchez J et al (2012) Using genome-wide complex trait analysis to quantify “missing heritability” in Parkinson’s disease. Hum Mol Genet 21(22):4996–5009

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  78. Evangelou E, Maraganore DM, Annesi G, Brighina L, Brice A, Elbaz A et al (2010) Non-replication of association for six polymorphisms from meta-analysis of genome-wide association studies of Parkinson’s disease: large-scale collaborative study. Am J Med Genet Part b, Neuropsychiatr Genet: Off Publ Int Soc Psychiatr Genet 153B(1):220–228

    CAS  Google Scholar 

  79. Tayebi N, Walker J, Stubblefield B, Orvisky E, LaMarca ME, Wong K et al (2003) Gaucher disease with parkinsonian manifestations: does glucocerebrosidase deficiency contribute to a vulnerability to parkinsonism? Mol Genet Metab 79(2):104–109

    Article  CAS  PubMed  Google Scholar 

  80. Neudorfer O, Giladi N, Elstein D, Abrahamov A, Turezkite T, Aghai E et al (1996) Occurrence of Parkinson’s syndrome in type I Gaucher disease. QJM: Mon J Assoc Physicians 89(9):691–694

    Article  CAS  Google Scholar 

  81. Tayebi N, Callahan M, Madike V, Stubblefield BK, Orvisky E, Krasnewich D et al (2001) Gaucher disease and Parkinsonism: a phenotypic and genotypic characterization. Mol Genet Metab 73(4):313–321

    Article  CAS  PubMed  Google Scholar 

  82. Neumann J, Bras J, Deas E, O’Sullivan SS, Parkkinen L, Lachmann RH et al (2009) Glucocerebrosidase mutations in clinical and pathologically proven Parkinson’s disease. Brain: J Neurol 132(Pt 7):1783–1794

    Article  Google Scholar 

  83. Sidransky E, Nalls M a, Aasly JO, Aharon-Peretz J, Annesi G, Barbosa ER et al (2009) Multicenter analysis of glucocerebrosidase mutations in Parkinson’s disease. N Engl J Med 361(17):1651–1661

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  84. Winder-Rhodes SE, Evans JR, Ban M, Mason SL, Williams-Gray CH, Foltynie T et al (2013) Glucocerebrosidase mutations influence the natural history of Parkinson’s disease in a community-based incident cohort. Brain: J Neurol 136(Pt 2):392–399

    Article  Google Scholar 

  85. McNeill A, Duran R, Hughes DA, Mehta A, Schapira AHV (2012) A clinical and family history study of Parkinson’s disease in heterozygous glucocerebrosidase mutation carriers. J Neurol Neurosurg Psychiatr 83(8):853–854

    Article  PubMed Central  PubMed  Google Scholar 

  86. Gegg ME, Burke D, Heales SJR, Cooper JM, Hardy J, Wood NW et al (2012) Glucocerebrosidase deficiency in substantia nigra of parkinson disease brains. Ann Neurol 72(3):455–463

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  87. Singleton A, Hardy J (2011) A generalizable hypothesis for the genetic architecture of disease: pleomorphic risk loci. Hum Mol Genet 20(2):158–162

    Article  Google Scholar 

  88. Deas E, Wood NW, Plun-Favreau H (2010) Mitophagy and Parkinson’s disease: the PINK1—parkin link. Biochim Biophys Acta 1813(4):623–633. doi:10.1016/j.bbamcr.2010.08.007

    Google Scholar 

  89. Whitworth AJ, Pallanck LJ (2009) The PINK1/Parkin pathway: a mitochondrial quality control system? J Bioenergetics Biomembranes 41(6):499–503

    Article  CAS  Google Scholar 

  90. Deas E, Plun-Favreau H, Gandhi S, Desmond H, Kjaer S, Loh SHY et al (2011) PINK1 cleavage at position A103 by the mitochondrial protease PARL. Hum Mol Genet 20(5):867–879

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  91. Sekine S, Kanamaru Y, Koike M, Nishihara A, Okada M, Kinoshita H et al (2012) Rhomboid protease PARL mediates the mitochondrial membrane potential loss-induced cleavage of PGAM5. J Biol Chem 287(41):34635–34645

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  92. Narendra D, Tanaka A, Suen D-F, Youle RJ (2008) Parkin is recruited selectively to impaired mitochondria and promotes their autophagy. J Cell Biol 183(5):795–803

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  93. Youle RJ, Narendra DP (2011) Mechanisms of mitophagy. Nat Rev Mol Cell Biol 12(1):9–14

    Article  CAS  PubMed  Google Scholar 

  94. Gegg ME, Cooper JM, Chau K-Y, Rojo M, Schapira AHV, Taanman J-W (2010) Mitofusin 1 and mitofusin 2 are ubiquitinated in a PINK1/parkin-dependent manner upon induction of mitophagy. Hum Mol Genet 19(24):4861–4870

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  95. Ziviani E, Tao RN, Whitworth AJ (2010) Drosophila parkin requires PINK1 for mitochondrial translocation and ubiquitinates mitofusin. Proc Natl Acad Sci USA 107(11):5018–5023

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  96. Narendra D, Walker JE, Youle R (2012) Mitochondrial quality control mediated by PINK1 and Parkin: links to parkinsonism. Cold Spring Harb Perspect Biol 4(11). doi:10.1101/cshperspect.a011338

  97. Liu S, Sawada T, Lee S, Yu W, Silverio G, Alapatt P et al (2012) Parkinson’s disease-associated kinase PINK1 regulates Miro protein level and axonal transport of mitochondria. PLoS Genet 8(3):e1002537

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  98. Wang X, Winter D, Ashrafi G, Schlehe J, Wong YL, Selkoe D et al (2011) PINK1 and parkin target miro for phosphorylation and degradation to arrest mitochondrial motility. Cell 147(4):893–906

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  99. Sun Y, Vashisht AA, Tchieu J, Wohlschlegel JA, Dreier L (2012) Voltage-dependent anion channels (VDACs) recruit Parkin to defective mitochondria to promote mitochondrial autophagy. J Biol Chem 287(48):40652–40660

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  100. Geisler S, Holmström KM, Skujat D, Fiesel FC, Rothfuss OC, Kahle PJ et al (2010) PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1. Nat Cell Biol 12(2):119–131

    Article  CAS  PubMed  Google Scholar 

  101. Mazzulli JR, Xu YH, Sun Y, Knight AL, McLean PJ, Caldwell GA, Sidransky E, Grabowski GA, Krainc D (2011) Gaucher disease glucocerebrosidase and α-synuclein form a bidirectional pathogenic loop in synucleinopathies. Cell 146(1):37–52. doi:10.1016/j.cell.2011.06.001

    Google Scholar 

  102. Holmans P, Moskvina V, Jones L, Sharma M, Vedernikov A, Buchel F et al (2013) A pathway-based analysis provides additional support for an immune-related genetic susceptibility to Parkinson’s disease. Hum Mol Genet 22(5):1039–1049

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  103. Saiki M, Baker A, Williams-Gray CH, Foltynie T, Goodman RS, Taylor CJ et al (2010) Association of the human leucocyte antigen region with susceptibility to Parkinson’s disease. J Neurol Neurosurg Psychiatr 81(8):890–891

    Article  PubMed  Google Scholar 

  104. McGeer PL, McGeer EG (2008) Glial reactions in Parkinson’s disease. Mov Disord: Off J Mov Disord Soc 23(4):474–483

    Article  Google Scholar 

  105. Charlesworth G, Gandhi S, Bras JM, Barker RA, Burn DJ, Chinnery PF et al (2012) Tau acts as an independent genetic risk factor in pathologically proven PD. Neurobiol Aging 33(4):838.e7–838.e11

    Article  CAS  Google Scholar 

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Acknowledgments

Our work is funded by Parkinson’s UK (Grants 8047 and J-1101) and the Medical Research Council UK (G0700943, G1100643).

Conflicts of interest

On behalf of all authors, the corresponding author states that there is no conflict of interest.

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Authors and Affiliations

  1. MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, Cardiff, CF14 4XN, UK

    Steven Lubbe & Huw R. Morris

  2. Neurology (C4), University Hospital of Wales, Cardiff, CF14 4XN, UK

    Huw R. Morris

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  1. Steven Lubbe
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  2. Huw R. Morris
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Correspondence to Huw R. Morris.

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Lubbe, S., Morris, H.R. Recent advances in Parkinson’s disease genetics. J Neurol 261, 259–266 (2014). https://doi.org/10.1007/s00415-013-7003-2

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  • DOI: https://doi.org/10.1007/s00415-013-7003-2

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