Genetic Analysis and Literature Review of SNCA Variants in Parkinson's Disease

Abstract

Parkinson's disease (PD) is the fastest-growing neurodegenerative disorder. Aging, environmental factors, and genetics are considered as risk factors. The alpha-synuclein gene (SNCA), the first pathogenic gene identified in a familial form of PD, was indisputably involved as a heritable component for familial and sporadic PD. In this study, whole-exome sequencing and Sanger sequencing were performed to evaluate the association between the SNCA gene variants and PD. The genetic data of 438 clinically diagnosed patients with PD and 543 matched control populations of the Han Chinese were analyzed. The literature review of SNCA variants for 231 cases reported in 89 articles was extracted from the PubMed and the Movement Disorder Society Genetic mutation database. No potentially causative variant(s) in the SNCA gene, excepting two single-nucleotide nonsynonymous variants c.158C>T (p.A53V, rs542171324) and c.349C>T (p.P117S, rs145138372), were detected. There was no statistically significant difference in the genotypic or allelic frequencies for either variant between the PD group and the control group (all P > 0.05). No copy number variants of the SNCA gene were detected. The results of this study suggest that the variants in the exons of the SNCA gene may have less or no role in the development of PD in the Han Chinese populations. The literature review suggests that psychiatric signs and cognitive decline/dementia were more common among patients with SNCA duplication or triplication (psychiatric signs: χ2 = 7.892, P = 0.005; cognitive decline/dementia: χ2 = 8.991, P = 0.003).

Modeling native and seeded Synuclein aggregation and related cellular dysfunctions in dopaminergic neurons derived by a new set of isogenic iPSC lines with SNCA multiplications

“…Patients with three SNCA copies manifest comparable disease onset and progression with those described in idiopathic forms, although they are more likely to develop cognitive decline and sleep disturbance [ 8 ]. In contrast, patients with SNCA triplication develop aggressive and early-onset parkinsonism, combined with additional non-motor signs, such as cognitive dysfunctions with features reminiscent of dementia with Lewy bodies [ 9 , 10 ]. These clinical presentations suggest that SNCA triplications cause a more severe phenotype than SNCA duplications, consistently with the underlying genetic defects.…”

Gene Co-expression Analysis of the Human Substantia Nigra Identifies ZNHIT1 as an SNCA Co-expressed Gene that Protects Against α-Synuclein-Induced Impairments in Neurite Growth and Mitochondrial Dysfunction in SH-SY5Y Cells

“…PD is a synucleinopathy characterised by the accumulation of intracellular proteinaceous aggregates, called Lewy bodies and Lewy neurites, which consist predominantly of the protein α-synuclein (α-Syn), which is encoded by the SNCA gene [5][6][7]. A definitive link between SNCA and PD came with the demonstration that mutations [8,9], or duplications and triplications [10,11], in SNCA cause autosomal-dominant PD and that genetic polymorphisms in SNCA are risk factors for sporadic PD [12][13][14][15][16]. Moreover, rodent neurons overexpressing αSyn [17], or iPSC-derived dopaminergic neurons carrying mutations, and duplications or triplications of SNCA have reduced survival and defects in neurite growth [18,19].…”

Parkinson’s Disease: Overview of Transcription Factor Regulation, Genetics, and Cellular and Animal Models

“…The first gene to be linked to PD was the SNCA gene which encodes the protein α-synuclein, a small protein of 16 kilodaltons (KD) ( Polymeropoulos et al, 1997 ). Both mutations in the coding sequence and entire duplications and triplications of the gene that alter gene dosage have been shown to cause PD ( Polymeropoulos et al, 1997 ; Meade et al, 2019 ; Guo et al, 2021 ). Thus, SNCA is a dosage-dependent gene.…”

“…The manner by which SNCA mutations and copy number variants cause PD is not precisely known ( Guo et al, 2021 ). However, mutations appear to impact the physiological role of the SNCA protein in terms of multimerization and by altering synaptic regulation and maturation, resulting in a reduction in dopamine (DA) in the striatum.…”