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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).
© 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. Background: Parkinson's disease (PD) is a complex multifactorial disorder with a genetic component in about 15% of cases. Multiplications and point mutations in SNCA gene, encoding α-synuclein (aSyn), are linked to rare familial forms of PD. Objective: Our goal was to assess the clinical presentation and the biological effects of a novel K58N aSyn mutation identified in a patient with PD. Methods: We describe the clinical presentation associated with the novel mutation, together with genetic testing through whole exome sequencing (WES). Furthermore, we conducted extensive biophysical and cellular assays to assess the functional consequences of this novel variant. Results: The patient exhibited typical features of sporadic PD with early onset and a benign disease course. WES showed a novel heterozygous missense variant in SNCA (NM_000345.4, c.174G>C; p.K58N). A positive family history of PD was evident, because both a parent and a grandparent had been diagnosed with PD but were deceased. The patient underwent deep brain stimulation surgery 13 years postdiagnosis, showing stable, long-term improvements in motor symptoms. Biophysical studies demonstrated K58N substitution causes local structural effects, disrupts membrane binding, and enhances aSyn in vitro aggregation. In cellular systems, K58N aSyn produces fewer inclusions per cell and does not form condensates. The variant increases aSyn cytoplasmic distribution and displays aberrant activity-dependent dynamic serine-129 phosphorylation. Conclusions: The clinical presentation associated with the novel K58N aSyn mutation suggests a relatively benign PD course consistent with the phenotypic spectrum of idiopathic PD. Overall, our molecular studies provide novel insight into the biology and pathobiology of aSyn. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Author(s): Al-Azzani M, Weber S, Ramalingam N, Ramon M, Shvachiy L, Mestre G, Zech M, Sicking K, de Opakua AI, Jayanthi V, Amaral L, Agarwal A, Chandran A, Chaves SR, Winkelmann J, Trenkwalder C, Schwager M, Pauli S, Dettmer U, Fernandez CO, Lautenschlager J, Zweckstetter M, Busnadiego RF, Mollenhauer B, Outeiro TF
Publication type: Article
Publication status: Published
Journal: Movement Disorders
Year: 2025
Pages: Epub ahead of print
Online publication date: 04/09/2025
Acceptance date: 15/08/2025
Date deposited: 16/09/2025
ISSN (print): 0885-3185
ISSN (electronic): 1531-8257
Publisher: John Wiley and Sons Inc.
URL: https://doi.org/10.1002/mds.70030
DOI: 10.1002/mds.70030
Data Access Statement: The main data generated or analyzed during this study are included in this article (and its Supporting Information files). 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 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 K58N mutant aSyn fibril are available under accession codes 9HXA (PDB) and EMD-52458 (EMDB). A comprehensive Key Resource Table, detailing datasets, software, and protocols, is available via Zenodo at: https://zenodo.org/records/14730688. [See the article for the full Data Availability Statement.]
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