244. Missense mutations in the SNCA gene: Molecular mechanisms and clinical implications

Article type: Literature Review
Article title: Missense mutations in the SNCA gene: Molecular mechanisms and clinical implications

Journal: Molecular and Cellular Neuroscience
Year: 2026
Authors: Pranaya Gade, Nishant Patel, Jamir Pitton Rissardo, Jorge Patino, Ana Letícia Fornari-Caprara, and Ian M. Walker

ABSTRACT
The SNCA gene on chromosome 4 encodes the alpha-synuclein (αSyn) protein, which plays a central role in the pathogenesis of synucleinopathies, including Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). While αSyn has established roles in synaptic vesicle dynamics and neuronal signaling, alterations in SNCA regulation and sequence contribute to protein misfolding, aggregation, and loss of function. Alterations in secondary and tertiary structure, as well as protein aggregation, affect biochemical interactions, ultimately leading to pathogenesis. This review outlines the molecular architecture of the SNCA gene, including regulatory regions, alternative splicing, and untranslated regions that influence αSyn expression and isoform diversity. Seven missense mutations of the SNCA gene are discussed in detail from the genomic level, extending to phenotypic presentations. These missense mutations have different effects on the aggregation kinetics and fibril formation. Specific genotype-phenotype correlations are evident, with mutations such as A30P and H50Q commonly resembling idiopathic PD, E46K strongly associated with DLB, and G51D, A53T, and A53E linked to atypical parkinsonism and MSA-like syndromes. Differences in age at onset, disease progression, cognitive involvement, and response to therapy further reflect mutation-specific effects and modifying influences of allelic dosage and epigenetic regulation. Collectively, these findings emphasize the importance of SNCA genetic variation in shaping disease phenotype and progression. Improving the understanding of SNCA genotype-phenotype relationships in future studies may facilitate earlier diagnosis, refine prognostic stratification, and support the development of targeted, disease-modifying therapies for synucleinopathies.

Keywords: synucleinopathy; neurodegeneration; protein aggregation; molecular mechanisms; pathogenic variants; structural modeling.

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DOI

Citation
Gade P, Patel N, Rissardo JP, Patino J, Fornari-Caprara AL, Walker IM. Missense mutations in the SNCA gene: Molecular mechanisms and clinical implications. Mol Cell Neurosci 2026;104116. doi:10.1016/j.mcn.2026.104116.
Figure 1. Genomic location of the SNCA gene on chromosome 4.
Figure 2. Genomic organization, regulatory elements, and major transcript isoforms of the SNCA gene. The SNCA transcript prior to alternative splicing consists of six exons separated by five introns and is flanked by 5’ and 3’ UTRs. Key regulatory elements, including the promoter region, CpG and non-CpG methylation sites, transcription factor binding sites, intronic epigenetic regulatory regions, and alternative polyadenylation of the 3’ UTR, are shown. Major transcript isoforms generated through alternative splicing (SNCA 140, SNCA 112, SNCA 126, SNCA 98) are also depicted.
Figure 3. Timeline of reported cases of SNCA missense mutation in chronological order. A timeline of SNCA missense mutation discovery and patient reports. The first mutation was discovered in 1997 and new mutations and cases were reported throughout the 20 years following the first discovery.
Figure 4. Structural features of αSyn protein. The alpha synuclein protein consists of a lysine-rich, amphipathic membranebinding N-terminus with residues 1 to 60, a central hydrophobic NAC region with residues 61 to 95, and a negatively charged C-terminus with residues 96-140. The heterozygous SNCA gene mutations, A53T, A30P, E46K, G51D, H50Q, A53E, and A53V, cluster within the N-terminus domain and the seven repeat KTKEGV sequences are located throughout the N-terminal region and NAC region (Blazekovic et al., 2021; Whittaker et al., 2017). Adapted from Whittaker et al. (2017). License: https://creativecommons.org/licenses/by/4.0/
Table 1. Clinical presentation of SNCA missense mutations.