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Fox Foundation for Parkinson's Research","doi-asserted-by":"publisher","award":["MJFF\u2010022411"],"award-info":[{"award-number":["MJFF\u2010022411"]}],"id":[{"id":"10.13039\/100000864","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["movementdisorders.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Movement Disorders"],"published-print":{"date-parts":[[2025,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Parkinson's disease (PD) is a complex multifactorial disorder with a genetic component in about 15% of cases. Multiplications and point mutations in\n                      <jats:italic>SNCA<\/jats:italic>\n                      gene, encoding \u03b1\u2010synuclein (aSyn), are linked to rare familial forms of PD.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>Our goal was to assess the clinical presentation and the biological effects of a novel K58N aSyn mutation identified in a patient with PD.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The patient exhibited typical features of sporadic PD with early onset and a benign disease course. WES showed a novel heterozygous missense variant in\n                      <jats:italic>SNCA<\/jats:italic>\n                      (NM_000345.4, c.174G&gt;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\u2009years postdiagnosis, showing stable, long\u2010term 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\u2010dependent dynamic serine\u2010129 phosphorylation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      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. \u00a9 2025 The Author(s).\n                      <jats:italic>Movement Disorders<\/jats:italic>\n                      published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/mds.70030","type":"journal-article","created":{"date-parts":[[2025,9,4]],"date-time":"2025-09-04T09:38:43Z","timestamp":1756978723000},"page":"2732-2745","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["A Novel \u03b1\u2010Synuclein\n                    <scp>K58N<\/scp>\n                    Missense Variant in a Patient with Parkinson's Disease"],"prefix":"10.1002","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2864-0854","authenticated-orcid":false,"given":"Mohammed","family":"Al\u2010Azzani","sequence":"first","affiliation":[{"name":"University Medical Center G\u00f6ttingen Department of Experimental Neurodegeneration, Center for Biostructural Imaging of Neurodegeneration  G\u00f6ttingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5713-2141","authenticated-orcid":false,"given":"Sandrina","family":"Weber","sequence":"additional","affiliation":[{"name":"Department of Neurology University Medical Center G\u00f6ttingen  G\u00f6ttingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9459-3593","authenticated-orcid":false,"given":"Nagendran","family":"Ramalingam","sequence":"additional","affiliation":[{"name":"Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and 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Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8112-9153","authenticated-orcid":false,"given":"Michael","family":"Zech","sequence":"additional","affiliation":[{"name":"Institute of Neurogenomics, Helmholtz Zentrum M\u00fcnchen, German Research Center for Environmental Health  Neuherberg Germany"},{"name":"Institute of Human Genetics, TUM School of Medicine and Health, Technical University of Munich  Munich Germany"},{"name":"Institute for Advanced Study, Technical University of Munich  Garching Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin","family":"Sicking","sequence":"additional","affiliation":[{"name":"University Medical Center G\u00f6ttingen, Institute for Neuropathology  G\u00f6ttingen Germany"},{"name":"Aligning Science Across Parkinson's (ASAP) Collaborative Research Network  Chevy Chase Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alain 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Centro de Estudios Interdisciplinarios, Universidad Nacional de Rosario  Rosario Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janin","family":"Lautenschl\u00e4ger","sequence":"additional","affiliation":[{"name":"Cambridge Institute for Medical Research, University of Cambridge, Cambridge Biomedical Campus  Cambridge United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus","family":"Zweckstetter","sequence":"additional","affiliation":[{"name":"German Center for Neurodegenerative Diseases  G\u00f6ttingen Germany"},{"name":"Department for NMR\u2010Based Structural Biology Max Planck Institute for Multidisciplinary Sciences  G\u00f6ttingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruben","family":"Fernandez\u2010Busnadiego","sequence":"additional","affiliation":[{"name":"University Medical Center G\u00f6ttingen, Institute for Neuropathology  G\u00f6ttingen Germany"},{"name":"Aligning Science Across 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