Molecular Genetics of Parkinsonism


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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Further Reading

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