PDF icon PDF herunterladen
Semin Neurol 2011; 31(5): 433-440
DOI: 10.1055/s-0031-1299782
© Thieme Medical Publishers

Genetics of Parkinson's Disease

Kishore R. Kumar1 , 2 , Ana Djarmati-Westenberger1 , Anne Grünewald1
  • 1Section of Clinical and Molecular Neurogenetics, Department of Neurology, University of Lübeck, Lübeck, Germany
  • 2Department of Neurogenetics, Kolling Institute of Medical Research, Royal North Shore Hospital and University of Sydney, Sydney, New South Wales, Australia
Weitere Informationen

Publikationsverlauf

Publikationsdatum:
21. Januar 2012 (online)

   Lizenzen und Reprints
Preview

ABSTRACT

The identification of genes contributing to Parkinson's disease (PD) has allowed for an improved understanding of the underlying pathogenesis of the disorder. The authors review the rapidly growing field of PD genetics, with a focus on the clinical, genetic, and pathophysiologic features of well-validated monogenic forms of PD caused by mutations in the SNCA, LRRK2, Parkin, PINK1, DJ-1, and ATP13A2 genes. In addition, they discuss mutations in the GBA gene, which increase susceptibility for PD. The authors also evaluate the implications of genome-wide association studies and stem cell-derived disease models and give recommendations for genetic testing.

KEYWORDS

Parkinson's disease - genetics - monogenic - genome-wide association study - stem cells

REFERENCES

  • 1 Polymeropoulos M H, Lavedan C, Leroy E et al.. Mutation in the alpha-synuclein gene identified in families with Parkinson's disease.  Science. 1997;  276 (5321) 2045-2047
    Suche in Google Scholar
  • 2 Spira P J, Sharpe D M, Halliday G, Cavanagh J, Nicholson G A. Clinical and pathological features of a parkinsonian syndrome in a family with an Ala53Thr alpha-synuclein mutation.  Ann Neurol. 2001;  49 (3) 313-319
    Suche in Google Scholar
  • 3 Nishioka K, Hayashi S, Farrer M J et al.. Clinical heterogeneity of alpha-synuclein gene duplication in Parkinson's disease.  Ann Neurol. 2006;  59 (2) 298-309
    Suche in Google Scholar
  • 4 Ross O A, Braithwaite A T, Skipper L M et al.. Genomic investigation of alpha-synuclein multiplication and parkinsonism.  Ann Neurol. 2008;  63 (6) 743-750
    Suche in Google Scholar
  • 5 Bertoncini C W, Fernandez C O, Griesinger C, Jovin T M, Zweckstetter M. Familial mutants of alpha-synuclein with increased neurotoxicity have a destabilized conformation.  J Biol Chem. 2005;  280 (35) 30649-30652
    Suche in Google Scholar
  • 6 Chen L, Feany M B. Alpha-synuclein phosphorylation controls neurotoxicity and inclusion formation in a Drosophila model of Parkinson disease.  Nat Neurosci. 2005;  8 (5) 657-663
    Suche in Google Scholar
  • 7 Brice A. Genetics of Parkinson's disease: LRRK2 on the rise.  Brain. 2005;  128 (Pt 12) 2760-2762
    Suche in Google Scholar
  • 8 Healy D G, Falchi M, O'Sullivan S S International LRRK2 Consortium et al. Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson's disease: a case-control study.  Lancet Neurol. 2008;  7 (7) 583-590
    Suche in Google Scholar
  • 9 Wszolek Z K, Pfeiffer R F, Tsuboi Y et al.. Autosomal dominant parkinsonism associated with variable synuclein and tau pathology.  Neurology. 2004;  62 (9) 1619-1622
    Suche in Google Scholar
  • 10 Lesage S, Leutenegger A L, Ibanez P French Parkinson's Disease Genetics Study Group et al. LRRK2 haplotype analyses in European and North African families with Parkinson disease: a common founder for the G2019S mutation dating from the 13th century.  Am J Hum Genet. 2005;  77 (2) 330-332
    Suche in Google Scholar
  • 11 Ozelius L J, Senthil G, Saunders-Pullman R et al.. LRRK2 G2019S as a cause of Parkinson's disease in Ashkenazi Jews.  N Engl J Med. 2006;  354 (4) 424-425
    Suche in Google Scholar
  • 12 Martin I, Dawson V L, Dawson T M. Recent advances in the genetics of Parkinson's disease.  Annu Rev Genomics Hum Genet. 2011;  12 301-325
    Suche in Google Scholar
  • 13 Smith W W, Pei Z, Jiang H, Dawson V L, Dawson T M, Ross C A. Kinase activity of mutant LRRK2 mediates neuronal toxicity.  Nat Neurosci. 2006;  9 (10) 1231-1233
    Suche in Google Scholar
  • 14 Lücking C B, Dürr A, Bonifati V French Parkinson's Disease Genetics Study Group et al. Association between early-onset Parkinson's disease and mutations in the parkin gene.  N Engl J Med. 2000;  342 (21) 1560-1567
    Suche in Google Scholar
  • 15 Klein C, Lohmann-Hedrich K. Impact of recent genetic findings in Parkinson's disease.  Curr Opin Neurol. 2007;  20 (4) 453-464
    Suche in Google Scholar
  • 16 Mori H, Kondo T, Yokochi M et al.. Pathologic and biochemical studies of juvenile parkinsonism linked to chromosome 6q.  Neurology. 1998;  51 (3) 890-892
    Suche in Google Scholar
  • 17 Hristova V A, Beasley S A, Rylett R J, Shaw G S. Identification of a novel Zn2+-binding domain in the autosomal recessive juvenile Parkinson-related E3 ligase parkin.  J Biol Chem. 2009;  284 (22) 14978-14986
    Suche in Google Scholar
  • 18 Henn I H, Bouman L, Schlehe J S et al.. Parkin mediates neuroprotection through activation of IkappaB kinase/nuclear factor-kappaB signaling.  J Neurosci. 2007;  27 (8) 1868-1878
    Suche in Google Scholar
  • 19 Palacino J J, Sagi D, Goldberg M S et al.. Mitochondrial dysfunction and oxidative damage in parkin-deficient mice.  J Biol Chem. 2004;  279 (18) 18614-18622
    Suche in Google Scholar
  • 20 Grünewald A, Voges L, Rakovic A et al.. Mutant parkin impairs mitochondrial function and morphology in human fibroblasts.  PLoS ONE. 2010;  5 (9) e12962
    Suche in Google Scholar
  • 21 Shin J H, Ko H S, Kang H et al.. PARIS (ZNF746) repression of PGC-1α contributes to neurodegeneration in Parkinson's disease.  Cell. 2011;  144 (5) 689-702
    Suche in Google Scholar
  • 22 Vives-Bauza C, Zhou C, Huang Y et al.. PINK1-dependent recruitment of Parkin to mitochondria in mitophagy.  Proc Natl Acad Sci U S A. 2010;  107 (1) 378-383
    Suche in Google Scholar
  • 23 Klein C, Djarmati A, Hedrich K et al.. PINK1, Parkin, and DJ-1 mutations in Italian patients with early-onset parkinsonism.  Eur J Hum Genet. 2005;  13 (9) 1086-1093
    Suche in Google Scholar
  • 24 Steinlechner S, Stahlberg J, Völkel B et al.. Co-occurrence of affective and schizophrenia spectrum disorders with PINK1 mutations.  J Neurol Neurosurg Psychiatry. 2007;  78 (5) 532-535
    Suche in Google Scholar
  • 25 Li Y, Tomiyama H, Sato K et al.. Clinicogenetic study of PINK1 mutations in autosomal recessive early-onset parkinsonism.  Neurology. 2005;  64 (11) 1955-1957
    Suche in Google Scholar
  • 26 Valente E M, Salvi S, Ialongo T et al.. PINK1 mutations are associated with sporadic early-onset parkinsonism.  Ann Neurol. 2004;  56 (3) 336-341
    Suche in Google Scholar
  • 27 Valente E M, Abou-Sleiman P M, Caputo V et al.. Hereditary early-onset Parkinson's disease caused by mutations in PINK1.  Science. 2004;  304 (5674) 1158-1160
    Suche in Google Scholar
  • 28 Clark I E, Dodson M W, Jiang C et al.. Drosophila pink1 is required for mitochondrial function and interacts genetically with parkin.  Nature. 2006;  441 (7097) 1162-1166
    Suche in Google Scholar
  • 29 Liu W, Acín-Peréz R, Geghman K D, Manfredi G, Lu B, Li C. Pink1 regulates the oxidative phosphorylation machinery via mitochondrial fission.  Proc Natl Acad Sci U S A. 2011;  108 (31) 12920-12924
    Suche in Google Scholar
  • 30 Pankratz N, Pauciulo M W, Elsaesser V E Parkinson Study Group - PROGENI Investigators et al. Mutations in DJ-1 are rare in familial Parkinson disease.  Neurosci Lett. 2006;  408 (3) 209-213
    Suche in Google Scholar
  • 31 Bonifati V, Rizzu P, van Baren M J et al.. Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism.  Science. 2003;  299 (5604) 256-259
    Suche in Google Scholar
  • 32 Takahashi-Niki K, Niki T, Taira T, Iguchi-Ariga S M, Ariga H. Reduced anti-oxidative stress activities of DJ-1 mutants found in Parkinson's disease patients.  Biochem Biophys Res Commun. 2004;  320 (2) 389-397
    Suche in Google Scholar
  • 33 Malgieri G, Eliezer D. Structural effects of Parkinson's disease linked DJ-1 mutations.  Protein Sci. 2008;  17 (5) 855-868
    Suche in Google Scholar
  • 34 Irrcher I, Aleyasin H, Seifert E L et al.. Loss of the Parkinson's disease-linked gene DJ-1 perturbs mitochondrial dynamics.  Hum Mol Genet. 2010;  19 (19) 3734-3746
    Suche in Google Scholar
  • 35 Ramirez A, Heimbach A, Gründemann J et al.. Hereditary parkinsonism with dementia is caused by mutations in ATP13A2, encoding a lysosomal type 5 P-type ATPase.  Nat Genet. 2006;  38 (10) 1184-1191
    Suche in Google Scholar
  • 36 Behrens M I, Brüggemann N, Chana P et al.. Clinical spectrum of Kufor-Rakeb syndrome in the Chilean kindred with ATP13A2 mutations.  Mov Disord. 2010;  25 (12) 1929-1937
    Suche in Google Scholar
  • 37 Park J S, Mehta P, Cooper A A et al.. Pathogenic effects of novel mutations in the P-type ATPase ATP13A2 (PARK9) causing Kufor-Rakeb syndrome, a form of early-onset parkinsonism.  Hum Mutat. 2011;  32 (8) 956-964
    Suche in Google Scholar
  • 38 Khan N L, Scherfler C, Graham E et al.. Dopaminergic dysfunction in unrelated, asymptomatic carriers of a single parkin mutation.  Neurology. 2005;  64 (1) 134-136
    Suche in Google Scholar
  • 39 Khan N L, Valente E M, Bentivoglio A R et al.. Clinical and subclinical dopaminergic dysfunction in PARK6-linked parkinsonism: an 18F-dopa PET study.  Ann Neurol. 2002;  52 (6) 849-853
    Suche in Google Scholar
  • 40 Vilariño-Güell C, Wider C, Ross O A et al.. VPS35 mutations in Parkinson disease.  Am J Hum Genet. 2011;  89 (1) 162-167
    Suche in Google Scholar
  • 41 Zimprich A, Benet-Pagès A, Struhal W et al.. A mutation in VPS35, encoding a subunit of the retromer complex, causes late-onset Parkinson disease.  Am J Hum Genet. 2011;  89 (1) 168-175
    Suche in Google Scholar
  • 42 Sidransky E, Nalls M A, Aasly J O et al.. Multicenter analysis of glucocerebrosidase mutations in Parkinson's disease.  N Engl J Med. 2009;  361 (17) 1651-1661
    Suche in Google Scholar
  • 43 Mazzulli J R, Xu Y H, Sun Y et al.. Gaucher disease glucocerebrosidase and α-synuclein form a bidirectional pathogenic loop in synucleinopathies.  Cell. 2011;  146 (1) 37-52
    Suche in Google Scholar
  • 44 Nalls M A, Plagnol V, Hernandez D G International Parkinson Disease Genomics Consortium et al. Imputation of sequence variants for identification of genetic risks for Parkinson's disease: a meta-analysis of genome-wide association studies.  Lancet. 2011;  377 (9766) 641-649
    Suche in Google Scholar
  • 45 Klein C, Ziegler A. From GWAS to clinical utility in Parkinson's disease.  Lancet. 2011;  377 (9766) 613-614
    Suche in Google Scholar
  • 46 Lill C M, Roehr J T, McQueen M B et al.. The PDGene database. Alzheimer research forum. Available at: http://www.pdgene.org/ Accessed December 8, 2011
    Suche in Google Scholar
  • 47 Harbo H F, Finsterer J, Baets J EFNS et al. EFNS guidelines on the molecular diagnosis of neurogenetic disorders: general issues, Huntington's disease, Parkinson's disease and dystonias.  Eur J Neurol. 2009;  16 (7) 777-785
    Suche in Google Scholar
  • 48 Jacobs H, Latza U, Vieregge A, Vieregge P. Attitudes of young patients with Parkinson's disease towards possible presymptomatic and prenatal genetic testing.  Genet Couns. 2001;  12 (1) 55-67
    Suche in Google Scholar
  • 49 Nguyen H N, Byers B, Cord B et al.. LRRK2 mutant iPSC-derived DA neurons demonstrate increased susceptibility to oxidative stress.  Cell Stem Cell. 2011;  8 (3) 267-280
    Suche in Google Scholar
  • 50 Seibler P, Graziotto J, Jeong H, Simunovic F, Klein C, Krainc D. Mitochondrial Parkin recruitment is impaired in neurons derived from mutant PINK1 induced pluripotent stem cells.  J Neurosci. 2011;  31 (16) 5970-5976
    Suche in Google Scholar
  • 51 Rhee Y H, Ko J Y, Chang M Y et al.. Protein-based human iPS cells efficiently generate functional dopamine neurons and can treat a rat model of Parkinson disease.  J Clin Invest. 2011;  121 (6) 2326-2335
    Suche in Google Scholar
  • 52 Caiazzo M, Dell'Anno M T, Dvoretskova E et al.. Direct generation of functional dopaminergic neurons from mouse and human fibroblasts.  Nature. 2011;  476 (7359) 224-227
    Suche in Google Scholar
  • 53 Nuytemans K, Theuns J, Cruts M, Van Broeckhoven C. Genetic etiology of Parkinson disease associated with mutations in the SNCA, PARK2, PINK1, PARK7, and LRRK2 genes: a mutation update.  Hum Mutat. 2010;  31 (7) 763-780
    Suche in Google Scholar
  • 54 Klein C, Schlossmacher M G. The genetics of Parkinson disease: implications for neurological care.  Nat Clin Pract Neurol. 2006;  2 (3) 136-146
    Suche in Google Scholar

Anne GrünewaldPh.D. 

Section of Clinical and Molecular Neurogenetics, Department of Neurology, University of Lübeck

Ratzeburger Allee 160, Lübeck 23538, Germany

eMail: anne.gruenewald@neuro.uni-luebeck.de