Parkinson's disease and α-synuclein expression

Abstract

Genetic studies of Parkinson's disease over the last decade or more have revolutionized our understanding of this condition. α-Synuclein was the first gene to be linked to Parkinson's disease, and is arguably the most important: the protein is the principal constituent of Lewy bodies, and variation at its locus is the major genetic risk factor for sporadic disease. Intriguingly, duplications and triplications of the locus, as well as point mutations, cause familial disease. Therefore, subtle alterations of α-synuclein expression can manifest with a dramatic phenotype. We outline the clinical impact of α-synuclein locus multiplications, and the implications that this has for Parkinson's disease pathogenesis. Finally, we discuss potential strategies for disease-modifying therapies for this currently incurable disorder.

FIG. 1

Multiple pathways promote accumulation and aggregation of α-synuclein. Gene multiplications and certain Rep1 polymorphisms can increase expression of α-synuclein directly. On the other hand, degradation of α-synuclein in the proteasome may be impaired by Parkin mutations. LRRK2 mutations can fragment Golgi, disrupting vesicular trafficking and thereby increasing α-synuclein in the soma. Mutations in glucocerebrosidase cause accumulation of glucocerebroside, which stabilizes oligomeric α-synuclein, enhancing fibril formation. In turn, α-synuclein impairs physiological glucocerebrosidase function. Multiple environmental toxins, including heavy metal cations, organic solvents and pesticides, can enhance misfolding and aggregation of α-synuclein. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]