Journal of Neurology

, Volume 261, Issue 2, pp 259–266

Recent advances in Parkinson’s disease genetics



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.


Parkinson’s disease Genetics  Genome wide-association study LRRK2 Parkin GBA 


  1. 1.
    Lees AJ, Hardy J, Revesz T (2009) Parkinson’s disease. Lancet 373(9680):2055–2066CrossRefPubMedGoogle Scholar
  2. 2.
    Goedert M, Spillantini MG, Del Tredici K, Braak H (2013) 100 years of Lewy pathology. Nat Rev Neurol 9(1):13–24CrossRefPubMedGoogle Scholar
  3. 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.)CrossRefPubMedGoogle Scholar
  4. 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):106–108CrossRefPubMedGoogle Scholar
  5. 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):164–173CrossRefPubMedGoogle Scholar
  6. 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.)CrossRefPubMedGoogle Scholar
  7. 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):571–576PubMedCentralCrossRefPubMedGoogle Scholar
  8. 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. 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 PubMedCentralCrossRefPubMedGoogle Scholar
  10. 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 PubMedCentralCrossRefPubMedGoogle Scholar
  11. 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. 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):663–672CrossRefPubMedGoogle Scholar
  13. 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):583–590PubMedCentralCrossRefPubMedGoogle Scholar
  14. 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):483–487CrossRefPubMedGoogle Scholar
  15. 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):422–423CrossRefPubMedGoogle Scholar
  16. 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):424–425CrossRefPubMedGoogle Scholar
  17. 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):595–600CrossRefPubMedGoogle Scholar
  18. 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):601–607CrossRefPubMedGoogle Scholar
  19. 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 6:32PubMedCentralCrossRefPubMedGoogle Scholar
  20. 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. 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 CrossRefPubMedGoogle Scholar
  22. 22.
    Lewis PA (2009) The function of ROCO proteins in health and disease. Biol Cell/Under Auspices Eur Cell Biol Organ 101(3):183–191CrossRefGoogle Scholar
  23. 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 PubMedCentralCrossRefPubMedGoogle Scholar
  24. 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):697–707CrossRefPubMedGoogle Scholar
  25. 25.
    Morris LGT, Veeriah S, Chan TA (2010) Genetic determinants at the interface of cancer and neurodegenerative disease. Oncogene 29(24):3453–3464PubMedCentralCrossRefPubMedGoogle Scholar
  26. 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):2536–2541CrossRefGoogle Scholar
  27. 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):162–167PubMedCentralCrossRefPubMedGoogle Scholar
  28. 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. 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):721–726PubMedCentralCrossRefPubMedGoogle Scholar
  30. 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.e5CrossRefGoogle Scholar
  31. 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):1413–1417CrossRefGoogle Scholar
  32. 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):398–406PubMedCentralCrossRefPubMedGoogle Scholar
  33. 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):19–22PubMedCentralCrossRefPubMedGoogle Scholar
  34. 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):982–989PubMedCentralCrossRefPubMedGoogle Scholar
  35. 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.e5CrossRefGoogle Scholar
  36. 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):281–285CrossRefPubMedGoogle Scholar
  37. 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 392:605–608CrossRefPubMedGoogle Scholar
  38. 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):1522–1529CrossRefPubMedGoogle Scholar
  39. 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):763–780PubMedCentralCrossRefPubMedGoogle Scholar
  40. 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):302–305CrossRefPubMedGoogle Scholar
  41. 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.)CrossRefPubMedGoogle Scholar
  42. 42.
    Schon E a, Przedborski S (2011) Mitochondria: the next (neurode) generation. Neuron 70(6):1033–1053PubMedCentralCrossRefPubMedGoogle Scholar
  43. 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):883–895CrossRefPubMedGoogle Scholar
  44. 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):689–702PubMedCentralCrossRefPubMedGoogle Scholar
  45. 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):1162–1166CrossRefPubMedGoogle Scholar
  46. 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):1157–1161CrossRefPubMedGoogle Scholar
  47. 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):627–638PubMedCentralCrossRefPubMedGoogle Scholar
  48. 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.)CrossRefPubMedGoogle Scholar
  49. 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):9103–9108PubMedCentralCrossRefPubMedGoogle Scholar
  50. 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):388–391CrossRefGoogle Scholar
  51. 51.
    Doherty KM, Silveira-Moriyama L, Parkkinen L, Healy DG, Farrell M, Mencacci NE et al (2013) Parkin disease: A clinicopathologic entity? JAMA Neurol 4:1–9Google Scholar
  52. 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):721–727PubMedCentralCrossRefPubMedGoogle Scholar
  53. 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):1184–1191CrossRefPubMedGoogle Scholar
  54. 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):4240–4246CrossRefGoogle Scholar
  55. 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):1791–1800CrossRefGoogle Scholar
  56. 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):19–23CrossRefPubMedGoogle Scholar
  57. 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):2415–2417CrossRefGoogle Scholar
  58. 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):240–245CrossRefPubMedGoogle Scholar
  59. 59.
    Deng H, Liang H, Jankovic J (2012) F-Box Only Protein 7 Gene in Parkinsonian-Pyramidal Disease. Archives Neurol 1:1–5Google Scholar
  60. 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):e28787PubMedCentralCrossRefPubMedGoogle Scholar
  61. 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):1308–1312PubMedCentralCrossRefPubMedGoogle Scholar
  62. 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):1303–1307CrossRefPubMedGoogle Scholar
  63. 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):370–384PubMedCentralCrossRefPubMedGoogle Scholar
  64. 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):593–605PubMedCentralCrossRefPubMedGoogle Scholar
  65. 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):97–109PubMedCentralCrossRefPubMedGoogle Scholar
  66. 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):781–785PubMedCentralCrossRefPubMedGoogle Scholar
  67. 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):615–627CrossRefPubMedGoogle Scholar
  68. 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):345–353PubMedCentralCrossRefPubMedGoogle Scholar
  69. 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):641–649CrossRefPubMedGoogle Scholar
  70. 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):e1002142CrossRefGoogle Scholar
  71. 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):e1002141PubMedCentralCrossRefPubMedGoogle Scholar
  72. 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 12:104PubMedCentralCrossRefPubMedGoogle Scholar
  73. 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.e13CrossRefGoogle Scholar
  74. 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):659–667PubMedCentralCrossRefPubMedGoogle Scholar
  75. 75.
    Hardy J, Singleton A (2009) Genomewide association studies and human disease. N Engl J Med 360(17):1759–1768PubMedCentralCrossRefPubMedGoogle Scholar
  76. 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):799–816CrossRefPubMedGoogle Scholar
  77. 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):4996–5009PubMedCentralCrossRefPubMedGoogle Scholar
  78. 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):220–228Google Scholar
  79. 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):104–109CrossRefPubMedGoogle Scholar
  80. 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):691–694CrossRefGoogle Scholar
  81. 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):313–321CrossRefPubMedGoogle Scholar
  82. 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):1783–1794CrossRefGoogle Scholar
  83. 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):1651–1661PubMedCentralCrossRefPubMedGoogle Scholar
  84. 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):392–399CrossRefGoogle Scholar
  85. 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):853–854PubMedCentralCrossRefPubMedGoogle Scholar
  86. 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):455–463PubMedCentralCrossRefPubMedGoogle Scholar
  87. 87.
    Singleton A, Hardy J (2011) A generalizable hypothesis for the genetic architecture of disease: pleomorphic risk loci. Hum Mol Genet 20(2):158–162CrossRefGoogle Scholar
  88. 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. 89.
    Whitworth AJ, Pallanck LJ (2009) The PINK1/Parkin pathway: a mitochondrial quality control system? J Bioenergetics Biomembranes 41(6):499–503CrossRefGoogle Scholar
  90. 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):867–879PubMedCentralCrossRefPubMedGoogle Scholar
  91. 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):34635–34645PubMedCentralCrossRefPubMedGoogle Scholar
  92. 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):795–803PubMedCentralCrossRefPubMedGoogle Scholar
  93. 93.
    Youle RJ, Narendra DP (2011) Mechanisms of mitophagy. Nat Rev Mol Cell Biol 12(1):9–14CrossRefPubMedGoogle Scholar
  94. 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):4861–4870PubMedCentralCrossRefPubMedGoogle Scholar
  95. 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):5018–5023PubMedCentralCrossRefPubMedGoogle Scholar
  96. 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. 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):e1002537PubMedCentralCrossRefPubMedGoogle Scholar
  98. 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):893–906PubMedCentralCrossRefPubMedGoogle Scholar
  99. 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):40652–40660PubMedCentralCrossRefPubMedGoogle Scholar
  100. 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):119–131CrossRefPubMedGoogle Scholar
  101. 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. 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):1039–1049PubMedCentralCrossRefPubMedGoogle Scholar
  103. 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):890–891CrossRefPubMedGoogle Scholar
  104. 104.
    McGeer PL, McGeer EG (2008) Glial reactions in Parkinson’s disease. Mov Disord: Off J Mov Disord Soc 23(4):474–483CrossRefGoogle Scholar
  105. 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.e11CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  1. 1.MRC Centre for Neuropsychiatric Genetics and GenomicsCardiff University School of MedicineCardiffUK
  2. 2.Neurology (C4)University Hospital of WalesCardiffUK

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