Genetics of Synucleinopathies

Abstract

Parkinson's disease (PD), diffuse Lewy body disease (DLBD), and multiple system atrophy (MSA) constitute the three major neurodegenerative disorders referred to as synucleinopathies because both genetic and pathological results implicate the α-synuclein protein in their pathogenesis. PD and DLBD are recognized as closely related diseases with substantial clinical and pathological overlap. MSA, on the other hand, has a distinctive clinical presentation and neuropathological profile. In this review, we will summarize the evidence linking α-synuclein to these three disorders. Hundreds of patients with point or copy number mutations in the gene encoding α-synuclein, SNCA, have been reported in the literature in association with hereditary, autosomal dominant forms of PD, DLBD, or neurodegenerative disease with parkinsonism. The copy number mutations show a dosage effect with age at onset and severity correlating with the number of extra copies of SNCA a patient carries. Common variation in and around the SNCA gene has also been found by genome-wide association studies to be associated with increased risk for apparently sporadic PD, with some evidence that these variants exert their effect through modest increases in α-synuclein expression. Complementing the genetic evidence linking α-synuclein to PD and DLBD is the pathological finding that α-synuclein is a major constituent of Lewy bodies and Lewy neurites in the brains of patients with the common sporadic form of PD. On the other hand, there is little genetic evidence linking SNCA to MSA despite strong neuropathological evidence of α-synuclein aggregation in oligodendroglial cells in MSA patients. Evidence is now emerging that α-synuclein aggregates can have different protein conformations, referred to as strains, similar to what has been shown in prion disease. The different phenotypes in hereditary PD/DLBD versus MSA are likely, therefore, to be the result not only of how specific mutations affect protein expression and turnover, but also a more complex interaction between intrinsic and extrinsic factors governing aggregation and strain formation.