Up-regulation of SNCA gene expression: implications to synucleinopathies

Abstract

Synucleinopathies are a group of neurodegenerative diseases that share a common pathological lesion of intracellular protein inclusions largely composed by aggregates of alpha-synuclein protein. Accumulating evidence, including genome wide association studies, has implicated alpha-synuclein (SNCA) gene in the etiology of synucleinopathies. However, the precise variants within SNCA gene that contribute to the sporadic form of Parkinson's Diseases (PD), Dementia with Lewy Bodies (DLB), Multiple System Atrophy (MSA) and other synucleinopathies, and their molecular mechanisms of action remain elusive. It has been suggested that SNCA expression levels are critical for the development of these diseases. Here we review several model systems that have been developed to advance the understanding of the role of SNCA expression levels in the etiology of synucleinopathies. We also describe different molecular mechanisms that regulate SNCA gene expression and discuss possible strategies for SNCA downregulation as means for therapeutic approaches. Finally, we highlight some examples that underscore the relationships between the genetic association findings and the regulatory mechanisms of SNCA expression, which suggest that genetic variability in SNCA locus is directly responsible, at least in part, to the changes in gene expression and explain the reported associations of SNCA with synucleinopathies. Future studies utilizing induced pluripotent stem cells (iPSCs)-derived neuronal lines and genome editing by CRISPR/Cas9, will allow us to validate, characterize, and manipulate the effects of particular cis-genetic variants on SNCA expression. Moreover, this model system will enable us to compare different neuronal and glia lineages involved in synucleinopathies representing an attractive strategy to elucidate – common and specific – SNCA -genetic variants, -regulatory mechanisms, and -vulnerable expression levels underlying synucleinopathy spectrum disorders. This forthcoming knowledge will support the development of precision medicine for synucleinopathies.

Genetic analysis of α‐synuclein 3′ untranslated region and its corresponding microRNAs in relation to Parkinson's disease compared to dementia with Lewy bodies

“…We suggest that cell-specific mechanisms regulate SNCA gene expression and involved the contribution of cis and trans acting factors[2]. Here as a pathology distinct cis factor we discovered a genetic variant in SNCA 3’UTR that specifically affect DLB risk and as a trans factor we found differential expression of miRNAs in pathology-relevant cells.…”

“…However, the molecular mechanism/s through which the 3' region of SNCA gene modulates the risk of developing sporadic PD remains to be determined. To date, accumulating evidence has been reported in both in vitro systems and in vivo models, suggesting that SNCA expression levels are critical for the development of the disease[2]. With the goal of understanding the genetic variation that underlies the observed association with the 3’ LD block of the SNCA gene we have been studying possible mechanisms that control gene expression in the context of the 3’ end of the gene.…”

Structural variants in SNCA gene and the implication to synucleinopathies

“…Over the last decade, genome wide association studies (GWAS) and candidate gene-based approaches 13 have implicated SNCA as a highly significant genetic risk factor for synucleinopathies including sporadic PD 14–27 , DLB 28 , MSA 2930 and LBV/AD 3132 . In addition, accumulating evidence from in vitro systems and in vivo models, suggesting that the α-syn expression levels are critical for the development of synucleinopathies (reviewed in 33 ). In this review, we will describe the contribution of both long and short SVs in the SNCA locus to the regulation of SNCA gene expression profiles, mRNA levels and splicing, in relation to their possible role in the etiology of synucleinopathies.…”

Towards a Non-Human Primate Model of Alpha-Synucleinopathy for Development of Therapeutics for Parkinson’s Disease: Optimization of AAV1/2 Delivery Parameters to Drive Sustained Expression of Alpha Synuclein and Dopaminergic Degeneration in Macaque

“…Evidence continues to support that Parkinson’s disease (PD) is an alpha-synucleinopathy [1–3]. Irrespective of etiology and varying upstream mechanisms, deposition of alpha-synuclein (aSyn) is a defining pathological feature of PD and is increasingly being understood to be involved in synaptic dysfunction [4–6] and axonal transport deficits [7, 8] and produces ER-Golgi stress [9, 10], to name a few key cell biological processes.…”