Structural variants in SNCA gene and the implication to synucleinopathies

•Structural variants (SVs) have a large impact on human complex diseases such as synucleinopathies, and also contribute significantly to variation in gene expression as exemplified here for SNCA gene.•Copy number variations (CNVs) of the SNCA gene cause familial Parkinson's disease (PD), where disease severity and the levels of wild-type SNCA mRNA and protein are correlated with SNCA gene dose.•A specific haplotype at a CT-rich region in SNCA-intron 4 that consists of a cluster of SSVs conferes risk to develop LBV/AD and acts as an enhancer element to increase SNCA-mRNA expression.•Rep1, a SSV ∼10 kb upstream of SNCA gene that comprises of a cluster of SSRs, has been associated with PD-risk and has a role in the regulation of SNCA transcription.•A polyT variant in SNCA-intron 2 influences the splicing efficiency of exon 3, deletion of this exon is differently expressed in synucleinopathies and has been suggested to lead to less protein aggregation.

Synucleinopathies are a group of neurodegenerative diseases that share a common pathological lesion of intracellular protein inclusions largely composed of aggregates of alpha-synuclein protein. Accumulating evidence, including genome-wide association studies, has implicated the alpha-synuclein (SNCA) gene in the etiology of synucleinopathies and it has been suggested that SNCA expression levels are critical for the development of these diseases. This review focuses on genetic variants from the class of structural variants (SVs), including multiplication of large genomic segments and short (<50 bp) genomic variants such as simple sequence repeats (SSRs), within the SNCA locus. We provide evidence that SNCA-SVs play a key role in the pathogenesis of synucleinopathies via their effects on gene expression and on regulatory mechanisms including transcription and splicing.