Chapter 2 - Alpha-synuclein gene and Parkinson's disease

Abstract

The α-synuclein (SNCA) gene encoding for the presynaptic neuronal protein α-synuclein is closely linked to Parkinson's disease (PD). Rare missense point mutations, such as the first genetic defect ever linked to PD, the p.A53T mutation, or multiplications of the SNCA gene locus lead to autosomal dominant familial PD. On the other hand, SNCA gene polymorphisms are linked to an increased risk for developing sporadic PD, as confirmed through large genome-wide association studies. In this review, we emphasize the link various SNCA mutations have to the disease, focusing on the various phenotypic features of the disease in mutation carriers, including relevant imaging approaches. Although the disease that develops in such carriers usually follows a typical course, there are notable exceptions to this rule in terms of severity or atypical features, which depend on the particular mutation and unexplained intrafamilial variability. The manner in which such mutations lead to the disease remains under investigation because there is no straightforward correlation of the resulting peptides with the aggregation potential.