Missense mutations in the SNCA gene: Molecular mechanisms and clinical implications.
Missense mutations in the SNCA gene: Molecular mechanisms and clinical implications.
Where did the research take place?
The study site has not been established. Author addresses may differ from where the research occurred.
Stratford, US · Author affiliation
Rowan School of Osteopathic Medicine of Rowan University, Stratford, NJ, 08084, USA. Electronic address: gadepr56@rowan.edu.Location evidence
Camden, US · Author affiliation
Neurology Department, Cooper University Hospital, Camden, NJ, 08103, USA. Electronic address: pittonrissardo-jamir@cooperhealth.edu.Location evidence
Cincinnati, US · Author affiliation
James J. and Joan A. Gardner Family Center for Parkinson's Disease and Movement Disorders, University of Cincinnati, Cincinnati, OH, USA. Electronic address: je.patino841@gmail.com.Location evidence
A plain-language reading has not been prepared for this paper yet.
Original 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.