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.

Transcriptional profiling of Multiple System Atrophy cerebellar tissue highlights differences between the parkinsonian and cerebellar sub-types of the disease

“…Additionally, SNCA was significantly downregulated after p-value combination in MSA-C (adj p < 0.05). The same result was found in another study [30], but not confirmed in other work [28,42]. Other studies based on oligodendrocyte isolation and qPCA analysis described a basal expression and a trend of an increased expression in MSA patients [4,19].…”

The Role of Alpha-Synuclein And Other Parkinson’s Genes in Neurodevelopmental and Neurodegenerative Disorders

“…α-syn (encoded by SNCA, NM_000345.3, OMIM *163890) is a key protein in the pathogenesis of PD and related α-synucleinopathies [120]. Since its discovery as the first PD-causing gene in 1997 [121][122][123], several missense mutations, a number of risk SNPs, small structural variants (SSV), and, recently, cases with SNCA multiplications and somatic mosaicism have been described [9,124,125]. Genomic duplications and triplications of various genomic sizes of the 4q22.1 genomic region are highly penetrant and contribute to PD, LBD, or multiple system atrophy (MSA).…”

“…Genomic duplications and triplications of various genomic sizes of the 4q22.1 genomic region are highly penetrant and contribute to PD, LBD, or multiple system atrophy (MSA). The critical genomic region of these cases spans the SNCA gene, which is the only gene overlapping in all described cases [9,[125][126][127]. While earlier studies used single PCR-based copy number analysis, comparative genomic hybridization (CGH) and optical mapping can now define the size of CNVs, breakpoints, and orientation much more accurately [128] (Figure S1, Table S3C).…”

Alpha-Synuclein Aggregation, Cholesterol Transport, and the 18-kDa Translocator Protein

“…Because of the genetic background of α-synucleinopathies, research must also be focused toward discovering the exact molecules and mechanisms for posttranscriptional and epigenetic regulation of SNCA gene. Up to this point, it is established that not only changes in the gene sequence (multiplications, missense mutations, and single nucleotide polymorphisms) but also activation of certain transcriptional factors and RNAs may affect α-Syn regular expression [38]. MicroRNAs (MiRNAs) are small non-coding RNA molecules encoded as independent genomic transcription units predominantly engaged as regulators of protein expression mostly through inhibition of mRNA translation or cleavage [39,40].…”