Journal Article

DZNE-2025-01413

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png A Novel α-Synuclein K58N Missense Variant in a Patient with Parkinson's Disease.

Al-Azzani, M. ; Weber, S. ; Ramalingam, N. ; Ramón, M. ; Shvachiy, L. ; Mestre, G. ; Zech, M. ; Sicking, K. ; de Opakua, A. I.DZNE* ; Jayanthi, V. ; Amaral, L. ; Agarwal, A. ; Chandran, A. ; Chaves, S. R. ; Winkelmann, J. ; Trenkwalder, C. ; Schwager, M. ; Pauli, S. ; Dettmer, U. ; Fernández, C. O. ; Lautenschläger, J. ; Zweckstetter, M.DZNE* ; Fernandez-Busnadiego, R. ; Mollenhauer, B.Extern* ; Outeiro, T. F. (Last author)DZNE*

2025
Wiley New York, NY

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Please use a persistent id in citations: doi:10.1002/mds.70030

Abstract: 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.Our goal was to assess the clinical presentation and the biological effects of a novel K58N aSyn mutation identified in a patient with PD.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.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.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.

Keyword(s): Humans (MeSH) ; alpha-Synuclein: genetics (MeSH) ; Parkinson Disease: genetics (MeSH) ; Mutation, Missense: genetics (MeSH) ; Male (MeSH) ; Female (MeSH) ; Middle Aged (MeSH) ; Exome Sequencing (MeSH) ; Pedigree (MeSH) ; Parkinson's disease ; genetics ; neurodegeneration ; protein aggregation ; α‐synuclein ; alpha-Synuclein ; SNCA protein, human

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Contributing Institute(s):

1. Epigenetics and Systems Medicine in Neurodegenerative Diseases (AG Fischer)
2. Translational Structural Biology (AG Zweckstetter)

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)

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Database coverage:
; ; ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; DEAL Wiley ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 5 ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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