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@ARTICLE{Brcke:281509,
      author       = {Brücke, Christof and Al-Azzani, Mohammed and Ramalingam,
                      Nagendran and Ramón, Maria and Sousa, Rita L and Buratti,
                      Fiamma and Zech, Michael and Sicking, Kevin and Amaral,
                      Leslie and Gelpi, Ellen and Chandran, Aswathy and Agarwal,
                      Aishwarya and Chaves, Susana R and Fernández, Claudio O and
                      Dettmer, Ulf and Lautenschläger, Janin and Zweckstetter,
                      Markus and Busnadiego, Ruben Fernandez and Zimprich,
                      Alexander and Outeiro, Tiago Fleming},
      title        = {{A} novel alpha-synuclein {G}14{R} missense variant is
                      associated with atypical neuropathological features.},
      journal      = {Molecular neurodegeneration},
      volume       = {20},
      number       = {1},
      issn         = {1750-1326},
      address      = {London},
      publisher    = {Biomed Central},
      reportid     = {DZNE-2025-01130},
      pages        = {98},
      year         = {2025},
      abstract     = {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.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.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.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.},
      keywords     = {Humans / alpha-Synuclein: genetics / Mutation, Missense:
                      genetics / Parkinson Disease: genetics / Parkinson Disease:
                      pathology / Male / Female / Pedigree / Aged / Middle Aged /
                      Exome Sequencing / Brain: pathology / Aggregation (Other) /
                      Alpha-synuclein (Other) / Bradykinesia (Other) / Dystonia
                      (Other) / Parkinson´s disease (Other) / alpha-Synuclein
                      (NLM Chemicals) / SNCA protein, human (NLM Chemicals)},
      cin          = {AG Fischer / AG Zweckstetter},
      ddc          = {570},
      cid          = {I:(DE-2719)1410002 / I:(DE-2719)1410001},
      pnm          = {352 - Disease Mechanisms (POF4-352)},
      pid          = {G:(DE-HGF)POF4-352},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:41013605},
      pmc          = {pmc:PMC12465293},
      doi          = {10.1186/s13024-025-00889-y},
      url          = {https://pub.dzne.de/record/281509},
}