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Lookup NU author(s): Professor Tiago OuteiroORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© The Author(s) 2025.Background: Parkinson’s disease (PD) affects millions of people worldwide, but only 5–10% of patients suffer from a monogenic forms of the disease with Mendelian inheritance. SNCA, the gene encoding for the protein alpha-synuclein (aSyn), was the first to be associated with familial forms of PD and, since then, several missense variants and multiplications of the gene have been established as rare causes of autosomal dominant forms of PD. In this study, we report the identification of a novel SNCA mutation in a patient that presented with a complex neurogenerative disorder, and unconventional neuropathological findings. We also performed in depth molecular studies of the effects of the novel aSyn mutation. Methods: A patient carrying the novel aSyn missense mutation and the family members were studied. We present the clinical features, genetic testing—whole exome sequencing (WES), and neuropathological findings. The functional consequences of this aSyn variant were extensively investigated using biochemical, biophysical, and cellular assays. Results: The patient exhibited a complex neurodegenerative disease that included generalized myocloni, bradykinesia, dystonia of the left arm and apraxia. WES identified a novel heterozygous SNCA variant (cDNA 40G > A; protein G14R). Neuropathological examination showed extensive atypical aSyn pathology with frontotemporal lobar degeneration (FTLD)-type distribution and nigral degeneration pattern with abundant ring-like neuronal inclusions, and few oligodendroglial inclusions. Sanger sequencing confirmed the SNCA variant in one healthy, 86-year-old parent of the patient suggesting incomplete penetrance. NMR studies suggest that the G14R mutation induces a local structural alteration in aSyn, and lower thioflavin T binding in in vitro fibrillization assays. Interestingly, the G14R aSyn fibers display different fibrillar morphologies than Lewy bodies as revealed by cryo-electron microscopy. Cellular studies of the G14R variant revealed increased inclusion formation, enhanced membrane association, and impaired dynamic reversibility of serine‐129 phosphorylation. Conclusions: The atypical neuropathological features observed, which are reminiscent of those observed for the G51D aSyn variant, suggest a causal role of the SNCA variant with a distinct clinical and pathological phenotype, which is further supported by the properties of the mutant aSyn.
Author(s): Brucke C, Al-Azzani M, Ramalingam N, Ramon M, Sousa RL, Buratti F, Zech M, Sicking K, Amaral L, Gelpi E, Chandran A, Agarwal A, Chaves SR, Fernandez CO, Dettmer U, Lautenschlager J, Zweckstetter M, Busnadiego RF, Zimprich A, Outeiro TF
Publication type: Article
Publication status: Published
Journal: Molecular Neurodegeneration
Year: 2025
Volume: 20
Issue: 1
Print publication date: 01/12/2025
Online publication date: 26/09/2025
Acceptance date: 16/08/2025
Date deposited: 13/10/2025
ISSN (electronic): 1750-1326
Publisher: BioMed Central Ltd
URL: https://doi.org/10.1186/s13024-025-00889-y
DOI: 10.1186/s13024-025-00889-y
Data Access Statement: The main data generated or analyzed during this study are included in this article (and its supplementary information files). Any additional that is not present in the manuscript will be available from the corresponding authors upon reasonable request. The micrographs used for the single-particle analysis (SPA) of aSyn fibrils are available in the EMPIAR database under accession code EMPIAR-12518. The atomic model and cryo-EM density map for the wild-type (WT) aSyn fibril are deposited in the Protein Data Bank (PDB) and Electron Microscopy Data Bank (EMDB) under accession codes 9HGS and EMD-52165, respectively. The corresponding data for the G14R mutant aSyn fibril are available under accession codes 9HGR (PDB) and EMD-52166 (EMDB). A comprehensive Key Resource Table, detailing datasets, software, and protocols is available via Zenodo at https://zenodo.org/records/14734406. For the remaining details please see the article’s data access statement
PubMed id: 41013605
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