Advancing Stem Cell Models of Alpha-Synuclein Gene Regulation in Neurodegenerative Disease

Abstract

Alpha-synuclein (non A4 component of amyloid precursor, SNCA, NM_000345.3) plays a central role in the pathogenesis of Parkinson's disease (PD) and related Lewy body disorders such as Parkinson's disease dementia, Lewy body dementia, and multiple system atrophy. Since its discovery as a disease-causing gene in 1997, alpha-synuclein has been a central point of scientific interest both at the protein and gene level. Mutations, including copy number variants, missense mutations, short structural variants, and single nucleotide polymorphisms, can be causative for PD and affect conformational changes of the protein, can contribute to changes in expression of alpha-synuclein and its isoforms, and can influence regulation of temporal as well as spatial levels of alpha-synuclein in different tissues and cell types. A lot of progress has been made to understand both the physiological transcriptional and epigenetic regulation of the alpha-synuclein gene and whether changes in transcriptional regulation could lead to disease and neurodegeneration in PD and related alpha-synucleinopathies. Although the histopathological changes in these neurodegenerative disorders are similar, the temporal and spatial presentation and progression distinguishes them which could be in part due to changes or disruption of transcriptional regulation of alpha-synuclein. In this review, we describe different genetic alterations that contribute to PD and neurodegenerative conditions and review aspects of transcriptional regulation of the alpha-synuclein gene in the context of the development of PD. New technologies, advanced gene engineering and stem cell modeling, are on the horizon to shed further light on a better understanding of gene regulatory processes and exploit them for therapeutic developments.

Keywords: Dementia with Lewy bodies; Parkinson's disease; SNCA; alpha-synuclein; induced pluripotent stem cells; transcriptional regulation.

Figure 1

UCSC Genome Browser custom tracks for PD-risk associated variants and regulatory regions impacting SNCA expression. (A) CNVs of SNCA locus on chromosome 4q21.23-q22.3 (GRCh37/hg19, chr4:84,239,011-98,739,011). Colors indicate gene copy numbers. Red: SNCA CNV triplications; blue: SNCA CNV duplications; combination: SNCA triplication (red) and duplication (blue); green: SNCA CNV deletions. IDs given to tracks were either based on family identifiers from literature or are first author's last name of publication where case/family has been reported. (B) Disease variants and regulatory regions of the SNCA genomic locus on chromosome 4q22.1 (GRCh37/hg19, chr4:90,608,984-90,793,984) (details in Supplementary Tables 2–4). Colors indicate functional changes related to variants. Red: total mRNA expression; blue: affects SNCA splice-isoform; green: SNCA methylation; pink: multiple associated functions. Additional tracks include microRNA and transcription factor binding sites, CpG islands, and integrated regulation from ENCODE (Layered H3K27Ac and DNase Clusters). (Supplementary Table 5 lists all positions to build custom tracks in UCSC Genome Browser).