{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,2,10]],"date-time":"2026-02-10T16:59:55Z","timestamp":1770742795118,"version":"3.49.0"},"posted":{"date-parts":[[2024,9,25]]},"group-title":"Neurology","reference-count":73,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2024,9,25]],"date-time":"2024-09-25T00:00:00Z","timestamp":1727222400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,2,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>\n                    Parkinson\u2019s disease (PD) affects millions of people worldwide, but only 5\u201310% of patients suffer from a monogenic form of the disease with Mendelian inheritance.\n                    <jats:italic>SNCA,<\/jats:italic>\n                    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\n                    <jats:italic>SNCA<\/jats:italic>\n                    gene have been established as rare causes of autosomal dominant forms of PD.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Aim and methods<\/jats:title>\n                  <jats:p>A patient carrying aSyn missense mutation and his 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.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    The patient exhibited a complex neurodegenerative disease that included generalized myocloni, bradykinesia, dystonia of the left arm and apraxia. WES identified a novel heterozygous\n                    <jats:italic>SNCA<\/jats:italic>\n                    variant (cDNA 40G&gt;A; protein G14R). Neuropathological examination showed extensive atypical aSyn pathology with frontotemporal lobar degeneration (FTLD) and nigral degeneration pattern with abundant ring-like neuronal inclusions, and few oligodendroglial inclusions. Sanger sequencing confirmed the\n                    <jats:italic>SNCA<\/jats:italic>\n                    variant in the healthy, elderly parent of the patient 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 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.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Summary<\/jats:title>\n                  <jats:p>\n                    The atypical neuropathological features observed, which are reminiscent of those observed for the G51D aSyn variant, suggest a causal role of the\n                    <jats:italic>SNCA<\/jats:italic>\n                    variant with a distinct clinical and pathological phenotype, which is further supported by the properties of the mutant aSyn, compatible with the strain hypothesis of proteinopathies.\n                  <\/jats:p>\n                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O.","family":"Fern\u00e1ndez","sequence":"additional","affiliation":[]},{"given":"Ulf","family":"Dettmer","sequence":"additional","affiliation":[]},{"given":"Janin","family":"Lautenschl\u00e4ger","sequence":"additional","affiliation":[]},{"given":"Markus","family":"Zweckstetter","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8366-7622","authenticated-orcid":false,"given":"Ruben Fernandez","family":"Busnadiego","sequence":"additional","affiliation":[]},{"given":"Alexander","family":"Zimprich","sequence":"additional","affiliation":[]},{"given":"Tiago Fleming","family":"Outeiro","sequence":"additional","affiliation":[]}],"member":"54368","reference":[{"key":"2025021003000455000_2024.09.23.24313864v3.1","first-page":"369","volume":"146","year":"2023","journal-title":"More than meets the eye in Parkinson\u2019s disease and other synucleinopathies: from proteinopathy to lipidopathy Acta 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