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.

Figure 1.

Schematic diagram of mutations in the SNCA gene causing Parkinson’s disease (PD) and diffuse Lewy body disease (DLBD). (A) Chromosome 4 showing location of the SNCA gene on 4q. Copy number mutations are shown that are either tandem duplications or triplications of the SNCA gene, resulting in patients with either three or four copies of the gene. (B) Schematic diagram of the SNCA mRNA showing exon boundaries. Arrows indicate the locations of eight well-established point mutations that cause PD, DLBD, or other neurodegenerative disorders in which parkinsonism is a major characteristic of the disease.

Figure 2.

Outline of clinical features associated with pathogenic SNCA mutations. Color scale from white to black is intended to denote increasing severity. For age at onset: (white) >60 yr, (gray) between 40 and 60 yr, and (black) <40 yr; for disease duration: (white) >15 yr, (gray) between 10 and 15 yr, and (black) <10 yr; for all other features: (white) absent, (gray) occasionally present, and (black) constantly present. Mutations are ordered from mildest (left) to most severe (right). (Reprinted, with permission, from Petrucci et al. 2016, © 2016 Elsevier.)