Molecular Genetics of Parkinsonism

Abstract

Over the past decade, genetic causes of parkinsonism have been elucidated, but in less than 10% of the cases. Since the discovery of the first gene responsible for Parkinson disease (PD), SCNA encoding α‐synuclein, linkage mapping and positional cloning have identified autosomal dominantly or recessively inherited PD‐causing mutations in the genes encoding parkin, PTEN‐induced kinase 1 (PINK1), DJ‐1, leucine‐rich repeat kinase 2 (LRRK2) and ATP13A2, indicating that PD has a highly heterogeneous aetiology. In addition, polymorphic variants in SNCA and LRRK2 and heterozygous mutations in the gene encoding β‐glucocerebrosidase (GBA) appear to contribute to sporadic PD in several populations. These mutations have been linked to mitochondrial dysfunction, accumulation of abnormal and misfolded proteins, impaired protein clearance and oxidative stress. Identification of other mendelian forms of PD will be the main challenge for the next decade.

Key concepts:

  • Deciphering the aetiology of monogenic forms of parkinsonism would help understanding of the common idiopathic forms of the disease.

  • Genetic dissection of familial parkinsonism provides clues in identifying pathways involved in neuronal death.

  • The knowledge of the pathogenesis of Parkinson disease at a molecular level will have important implications for the development of individual therapeutic strategies to prevent disease progression.

  • Linkage analysis and positional cloning are fundamental tools for identifying genes in inherited diseases.

  • Genome‐wide association studies provide a powerful tool to identify low penetrance at‐risk alleles.

Keywords: parkinsonism; monogenic forms; autosomal dominant forms; autosomal recessive forms; common sporadic forms; susceptibility factors; clinical and genetic heterogeneity

Figure 1.

Worldwide distribution of the LRRK2 p.G2019S mutation in familial and sporadic PD. The frequencies of the LRRK2 p.G2019S mutation are indicated in pink for familial cases and in blue in brackets for sporadic cases.

Figure 2.

Distribution of the LRRK2 p.G2019S mutation in familial and sporadic PD across different European countries. The frequencies of the LRRK2 p.G2019S mutation are indicated in pink for familial cases and in blue in brackets for sporadic cases.

Figure 3.

Flow chart to prioritise PD‐associated genes for genetic testing according to family history, age at disease onset and ethnic origin. Males are represented by a square and females by a circle. Individuals affected with PD are represented with black symbols, unaffected with open symbols. SNCA, α‐synuclein; PINK1, PTEN‐induced kinase 1; LRRK2, leucine‐rich repeat kinase.

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References

Bonifati V (2009) Is GIGYF2 the defective gene at the PARK11 locus? Current Neurology and Neuroscience Reports 9: 185–187.

Bonifati V, Rizzu P, van Baren MJ et al. (2003) Mutations in the DJ‐1 gene associated with autosomal recessive early onset parkinsonism. Science (New York) 299: 256–259.

Canet‐Aviles RM, Wilson MA, Miller DW et al. (2004) The Parkinson's disease protein DJ‐1 is neuroprotective due to cysteine‐sulfinic acid‐driven mitochondrial localization. Proceedings of the National Academy of Sciences of the USA 101: 9103–9108.

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

Darios F, Corti O, Lucking CB et al. (2003) Parkin prevents mitochondrial swelling and cytochrome c release in mitochondria‐dependent cell death. Human Molecular Genetics 12: 517–526.

Di Fonzo A, Chien HF, Socal M et al. (2007) ATP13A2 missense mutations in juvenile parkinsonism and young onset Parkinson disease. Neurology 68: 1557–1562.

Di Fonzo A, Dekker MC, Montagna P et al. (2009) FBXO7 mutations cause autosomal recessive, early onset parkinsonian‐pyramidal syndrome. Neurology 72: 240–245.

van Duijn CM, Dekker MC, Bonifati V et al. (2001) Park7, a novel locus for autosomal recessive early onset parkinsonism, on chromosome 1p36. American Journal of Human Genetics 69: 629–634.

Funayama M, Hasegawa K, Kowa H et al. (2002) A new locus for Parkinson's disease (PARK8) maps to chromosome 12p11.2‐q13.1. Annals of neurology 51: 296–301.

Fung HC, Scholz S, Matarin M et al. (2006) Genome‐wide genotyping in Parkinson's disease and neurologically normal controls: first stage analysis and public release of data. Lancet Neurology 5: 911–916.

Gan‐Or Z, Giladi N, Rozovski U et al. (2008) Genotype‐phenotype correlations between GBA mutations and Parkinson disease risk and onset. Neurology 70: 2277–2283.

Gasser T, Muller‐Myhsok B, Wszolek ZK et al. (1998) A susceptibility locus for Parkinson's disease maps to chromosome 2p13. Nature Genetics 18: 262–265.

Gwinn‐Hardy K, Chen JY, Liu HC et al. (2000) Spinocerebellar ataxia type 2 with parkinsonism in ethnic Chinese. Neurology 55: 800–805.

Hampe C, Ardila‐Osorio H, Fournier M et al. (2006) Biochemical analysis of Parkinson's disease‐causing variants of Parkin, an E3 ubiquitin‐protein ligase with monoubiquitylation capacity. Human Molecular Genetics 15: 2059–2075.

Healy DG, Falchi M, O'sullivan SS et al. (2008) Phenotype, genotype, and worldwide genetic penetrance of LRRK2‐associated Parkinson's disease: a case‐control study. Lancet Neurology 7: 583–590.

Hicks AA, Petursson H, Jonsson T et al. (2002) A susceptibility gene for late‐onset idiopathic Parkinson's disease. Annals of Neurology 52: 549–555.

Kitada T, Asakawa S, Hattori N et al. (1998) Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 392: 605–608.

Kruger R, Kuhn W, Muller T et al. (1998) Ala30Pro mutation in the gene encoding alpha‐synuclein in Parkinson's disease. Nature Genetics 18: 106–108.

Lashuel HA, Hartley D, Petre BM et al. (2002) Neurodegenerative disease: amyloid pores from pathogenic mutations. Nature 418: 291.

Lautier C, Goldwurm S, Durr A et al. (2008) Mutations in the GIGYF2 (TNRC15) gene at the PARK11 locus in familial Parkinson disease. American Journal of Human Genetics 82: 822–833.

Leroy E, Boyer R, Auburger G et al. (1998) The ubiquitin pathway in Parkinson's disease. Nature 395: 451–452.

Lohmann E, Periquet M, Bonifati V et al. (2003) How much phenotypic variation can be attributed to parkin genotype? Annals of Neurology 54: 176–185.

Lwin A, Orvisky E, Goker‐Alpan O et al. (2004) Glucocerebrosidase mutations in subjects with parkinsonism. Molecular Genetics and Metabolism 81: 70–73.

Maraganore DM, de Andrade M, Elbaz A et al. (2006) Collaborative analysis of alpha‐synuclein gene promoter variability and Parkinson disease. JAMA 296: 661–670.

Maraganore DM, de Andrade M, Lesnick TG et al. (2005) High‐resolution whole‐genome association study of Parkinson disease. American Journal of Human Genetics 77: 685–693.

Maraganore DM, Lesnick TG, Elbaz A et al. (2004) UCHL1 is a Parkinson's disease susceptibility gene. Annals of Neurology 55: 512–521.

Moore DJ (2006) Parkin: a multifaceted ubiquitin ligase. Biochemical Society Transactions 34: 749–753.

Paisan‐Ruiz C, Bhatia KP, Li A et al. (2009) Characterization of PLA2G6 as a locus for dystonia‐parkinsonism. Annals of Neurology 65: 19–23.

Paisan‐Ruiz C, Jain S, Evans EW et al. (2004) Cloning of the gene containing mutations that cause PARK8‐linked Parkinson's disease. Neuron 44: 595–600.

Pankratz N, Nichols WC, Uniacke SK et al. (2002) Genome screen to identify susceptibility genes for Parkinson disease in a sample without parkin mutations. American Journal of Human Genetics 71: 124–135.

Pankratz N, Nichols WC, Uniacke SK et al. (2003) Significant linkage of Parkinson disease to chromosome 2q36‐37. American Journal of Human Genetics 72: 1053–1057.

Plun‐Favreau H, Klupsch K, Moisoi N et al. (2007) The mitochondrial protease HtrA2 is regulated by Parkinson's disease‐associated kinase PINK1. Nature Cell Biology 9: 1243–1252.

Polymeropoulos MH, Higgins JJ, Golbe LI et al. (1996) Mapping of a gene for Parkinson's disease to chromosome 4q21–q23. Science (New York) 274: 1197–1199.

Polymeropoulos MH, Lavedan C, Leroy E et al. (1997) Mutation in the alpha‐synuclein gene identified in families with Parkinson's disease. Science (New York) 276: 2045–2047.

Pridgeon JW, Olzmann JA, Chin LS et al. (2007) PINK1 protects against oxidative stress by phosphorylating mitochondrial chaperone TRAP1. PLoS Biology 5: e172.

Ramirez A, Heimbach A, Grundemann J et al. (2006) Hereditary parkinsonism with dementia is caused by mutations in ATP13A2, encoding a lysosomal type 5 P‐type ATPase. Nature Genetics 38: 1184–1191.

Ross OA, Braithwaite AT, Skipper LM et al. (2008) Genomic investigation of alpha‐synuclein multiplication and parkinsonism. Annals of Neurology 63: 743–750.

Satake W, Nakabayashi Y, Mizuta I et al. (2009) Genome‐wide association study identifies common variants at four loci as genetic risk factors for Parkinson's disease. Nature Genetics 41: 1303–1307.

Sharma M, Mueller JC, Zimprich A et al. (2006) The sepiapterin reductase gene region reveals association in the PARK3 locus: analysis of familial and sporadic Parkinson's disease in European populations. Journal of Medical Genetics 43: 557–562.

Shojaee S, Sina F, Banihosseini SS et al. (2008) Genome‐wide linkage analysis of a parkinsonian‐pyramidal syndrome pedigree by 500 K SNP arrays. American Journal of Human Genetics 82: 1375–1384.

Sidransky E, Nalls MA, Aasly JO et al. (2009) Multicenter analysis of glucocerebrosidase mutations in Parkinson's disease. New England Journal of Medicine 361: 1651–1661.

Simon‐Sanchez J and Singleton AB (2008) Sequencing analysis of OMI/HTRA2 shows previously reported pathogenic mutations in neurologically normal controls. Human Molecular Genetics 17: 1988–1993.

Singleton AB, Farrer M, Johnson J et al. (2003) Alpha‐synuclein locus triplication causes Parkinson's disease. Science (New York) 302: 841.

Spillantini MG, Schmidt ML, Lee VM et al. (1997) Alpha‐synuclein in Lewy bodies. Nature 388: 839–840.

Strauss KM, Martins LM, Plun‐Favreau H et al. (2005) Loss of function mutations in the gene encoding Omi/HtrA2 in Parkinson's disease. Human Molecular Genetics 14: 2099–2111.

Tang B, Xiong H, Sun P et al. (2006) Association of PINK1 and DJ‐1 confers digenic inheritance of early onset Parkinson's disease. Human Molecular Genetics 15: 1816–1825.

Valente EM, Abou‐Sleiman PM, Caputo V et al. (2004) Hereditary early onset Parkinson's disease caused by mutations in PINK1. Science (New York) 304: 1158–1160.

Yang Y, Gehrke S, Imai Y et al. (2006) Mitochondrial pathology and muscle and dopaminergic neuron degeneration caused by inactivation of Drosophila Pink1 is rescued by Parkin. Proceedings of the National Academy of Sciences of the USA 103: 10793–10798.

Zabetian CP, Hutter CM, Factor SA et al. (2007) Association analysis of MAPT H1 haplotype and subhaplotypes in Parkinson's disease. Annals of Neurology 62: 137–144.

Zabetian CP, Hutter CM, Yearout D et al. (2006) LRRK2 G2019S in families with Parkinson disease who originated from Europe and the Middle East: evidence of two distinct founding events beginning two millennia ago. American Journal of Human Genetics 79: 752–758.

Zabetian CP, Yamamoto M, Lopez AN et al. (2009) LRRK2 mutations and risk variants in Japanese patients with Parkinson's disease. Movement Disorders 24: 1034–1041.

Zarranz JJ, Alegre J, Gomez‐Esteban JC et al. (2004) The new mutation, E46K, of alpha‐synuclein causes Parkinson and Lewy body dementia. Annals of Neurology 55: 164–173.

Zimprich A, Biskup S, Leitner P et al. (2004) Mutations in LRRK2 cause autosomal‐dominant parkinsonism with pleomorphic pathology. Neuron 44: 601–607.

Further Reading

Cook C and Petrucelli L (2009) A critical evaluation of the ubiquitin‐proteasome system in Parkinson's disease. Biochimica et Biophysica Acta 1792: 664–675.

Cookson MR (2009) Alpha‐synuclein and neuronal cell death. Molecular Neurodegeneration 4: 9.

Cookson MR, Dauer W, Dawson T et al. (2007) The roles of kinases in familial Parkinson's disease. Journal of Neuroscience 27: 11865–11868.

Dodson MW and Guo M (2007) Pink1, Parkin, DJ‐1 and mitochondrial dysfunction in Parkinson's disease. Current Opinion in Neurobiology 17: 331–337.

Gasser T (2009a) Genomic and proteomic biomarkers for Parkinson disease. Neurology 72: S27–S31.

Gasser T (2009b) Mendelian forms of Parkinson's disease. Biochimica et Biophysica Acta 1792: 587–596.

Henchcliffe C and Beal MF (2008) Mitochondrial biology and oxidative stress in Parkinson disease pathogenesis. Nature Clinical Practice 4: 600–609.

Klein C, Lohmann‐Hedrich K, Rogaeva E et al. (2007) Deciphering the role of heterozygous mutations in genes associated with parkinsonism. Lancet Neurology 6: 652–662.

Klein C and Schlossmacher MG (2006) The genetics of Parkinson disease: Implications for neurological care. Nature Clinical Practice 2: 136–146.

Luzon‐Toro B, Rubio de la Torre E, Delgado A et al. (2007) Mechanistic insight into the dominant mode of the Parkinson's disease‐associated G2019S LRRK2 mutation. Human Molecular Genetics 16: 2031–2039.

Tan EK (2007) The role of common genetic risk variants in Parkinson disease. Clinical Genetics 72: 387–393.

van der Vegt JP, van Nuenen BF, Bloem BR et al. (2009) Imaging the impact of genes on Parkinson's disease. Neuroscience 164: 191–204.

Yang Y and Lu B (2009) Mitochondrial morphogenesis, distribution, and Parkinson disease: insights from PINK1. Journal of Neuropathology and Experimental Neurology 68: 953–963.

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Lesage, Suzanne, and Brice, Alexis(May 2010) Molecular Genetics of Parkinsonism. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0022386]