Synucleinopathies, including Parkinson's disease (PD), dementia with Lewy bodies, and multiple system atrophy (MSA), are a group of neurodegenerative diseases characterized by the oligomerization of α-synuclein protein in neurons or glial cells. Various splicing isoforms of α-synuclein have been described, each with different aggregation properties. The α-synuclein gene (SNCA) has been identified as a highly significant genetic risk locus associated with various synucleinopathies across populations. This study aimed to assess the association of SNCA genetic variants with MSA and the levels of SNCA transcripts in peripheral blood mononuclear cells (PBMCs) from MSA and PD patients.
Methods
In this retrospective case–control study, 96 MSA patients, 1086 PD patients, and 485 healthy volunteers were included. PCR followed by restriction endonuclease analysis was used to detect four SNCA single-nucleotide polymorphisms (rs356219, rs3756063, rs11931074, and rs356168) in these individuals. In addition, RT-qPCR was performed to detect the levels of α-synuclein transcripts (SNCA mRNA isoforms -140, -126, and -112) in PBMCs of 24 MSA patients (including parkinsonian (MSA-P) and cerebellar (MSA-C) variants), 31 PD patients, and 32 healthy volunteers.
Results
The frequency of the 'T' allele (of rs11931074) was significantly higher in MSA patients than in the healthy controls. The level of SNCA-140 mRNA was significantly decreased in MSA and PD patients compared with the controls, while the level of SNCA-112 mRNA was significantly increased in MSA-P patients than in PD patients and the controls. SNCA-112 mRNA/SNCA-140 mRNA and SNCA-112 mRNA/SNCA-126 mRNA ratios were significantly increased in MSA patients than in the controls.
Conclusions
This study confirmed the association of the SNCA rs11931074 polymorphism with MSA as well as the significance of the SNCA locus in MSA development. The pronounced alteration in the expression of SNCA transcripts in PBMCs of MSA patients found in this study highlights the importance of analyzing different SNCA transcript variants, rather than total SNCA, in biomarker research and may contribute to understanding the specific role of α-synuclein transcripts in the pathogenesis of MSA and PD. Our results also provide unique insights into the complexity of SNCA transcription and strengthen the relevance of SNCA splicing isoforms to MSA pathology.
Full text
https://www.xiahepublishing.com/1555-3884/GE-2025-00091
The study was recently published in the Gene Expression .
Gene Expression (GE) is an open-access journal. It was launched in 1991 by Chicago Medical School Press, and transferred to Cognizant Communication Corporation in 1994. From August 2022, GE is published by Xia & He Publishing Inc.
GE publishes peer-reviewed and high-quality original articles, reviews, editorials, commentaries, and opinions on its primary research topics including cell biology, molecular biology, genes, and genetics, especially on the cellular and molecular mechanisms of human diseases.
GE has been indexed in Medline (1991-2021), Scopus, Biological Abstracts, Biosis Previews, ProQuest, etc.
