A Novel α-Synuclein K58N Missense Variant in a Patient with Parkinson's Disease

Mohammed Al-Azzani¹, Sandrina Weber², Nagendran Ramalingam³, Maria Ramón¹, Liana Shvachiy¹, Gonçalo Mestre¹, Michael Zech^{4

5

6}, Kevin Sicking^{7

8}, Alain Ibáñez de Opakua⁹, Vidyashree Jayanthi³, Leslie Amaral^{1

10}, Aishwarya Agarwal¹¹, Aswathy Chandran¹¹, Susana R Chaves¹⁰, Juliane Winkelmann^{4

5

12

13}, Claudia Trenkwalder^{14

15}, Maike Schwager¹⁶, Silke Pauli¹⁶, Ulf Dettmer³, Claudio O Fernández¹⁷, Janin Lautenschläger¹¹, Markus Zweckstetter^{9

18}, Ruben Fernandez Busnadiego^{7

8

19

20}, Brit Mollenhauer^{2

15}, Tiago Fleming Outeiro^{1

9

21

22}

Affiliations

¹ University Medical Center Göttingen, Department of Experimental Neurodegeneration, Center for Biostructural Imaging of Neurodegeneration, Göttingen, Germany.
² Department of Neurology, University Medical Center Göttingen, Göttingen, Germany.
³ Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
⁴ Institute of Neurogenomics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
⁵ Institute of Human Genetics, TUM School of Medicine and Health, Technical University of Munich, Munich, Germany.
⁶ Institute for Advanced Study, Technical University of Munich, Garching, Germany.
⁷ University Medical Center Göttingen, Institute for Neuropathology, Göttingen, Germany.
⁸ Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, Maryland, USA.
⁹ German Center for Neurodegenerative Diseases, Göttingen, Germany.
¹⁰ CBMA-Centre of Molecular and Environmental Biology, School of Sciences, University of Minho, Braga, Portugal.
¹¹ Cambridge Institute for Medical Research, University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom.
¹² Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
¹³ German Center for Mental Health (DZPG), partner site Munich-Augsburg, Munich-Augsburg, Germany.
¹⁴ Department of Neurosurgery, University Medical Centre Göttingen, Göttingen, Germany.
¹⁵ Paracelsus-Elena-Klinik, Kassel, Germany.
¹⁶ Institute of Human Genetics, University Medical Center Göttingen, Göttingen, Germany.
¹⁷ Max Planck Laboratory for Structural Biology, Chemistry and Molecular Biophysics of Rosario (MPLbioR, UNR-MPINAT), Partner Laboratory of the Max Planck Institute for Multidisciplinary Sciences (MPINAT, MPG). Centro de Estudios Interdisciplinarios, Universidad Nacional de Rosario, Rosario, Argentina.
¹⁸ Department for NMR-Based Structural Biology, Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany.
¹⁹ Cluster of Excellence "Multiscale Bioimaging: From Molecular Machines to Networks of Excitable Cells," University of Göttingen, Göttingen, Germany.
²⁰ Faculty of Physics, University of Göttingen, Göttingen, Germany.
²¹ Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne, United Kingdom.
²² Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany.

PMID: 40905240
DOI: 10.1002/mds.70030

A Novel α-Synuclein K58N Missense Variant in a Patient with Parkinson's Disease

Mohammed Al-Azzani et al. Mov Disord. 2025.

. 2025 Sep 4.

doi: 10.1002/mds.70030. Online ahead of print.

Authors

Affiliations

¹ University Medical Center Göttingen, Department of Experimental Neurodegeneration, Center for Biostructural Imaging of Neurodegeneration, Göttingen, Germany.
² Department of Neurology, University Medical Center Göttingen, Göttingen, Germany.
³ Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
⁴ Institute of Neurogenomics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
⁵ Institute of Human Genetics, TUM School of Medicine and Health, Technical University of Munich, Munich, Germany.
⁶ Institute for Advanced Study, Technical University of Munich, Garching, Germany.
⁷ University Medical Center Göttingen, Institute for Neuropathology, Göttingen, Germany.
⁸ Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, Maryland, USA.
⁹ German Center for Neurodegenerative Diseases, Göttingen, Germany.
¹⁰ CBMA-Centre of Molecular and Environmental Biology, School of Sciences, University of Minho, Braga, Portugal.
¹¹ Cambridge Institute for Medical Research, University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom.
¹² Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
¹³ German Center for Mental Health (DZPG), partner site Munich-Augsburg, Munich-Augsburg, Germany.
¹⁴ Department of Neurosurgery, University Medical Centre Göttingen, Göttingen, Germany.
¹⁵ Paracelsus-Elena-Klinik, Kassel, Germany.
¹⁶ Institute of Human Genetics, University Medical Center Göttingen, Göttingen, Germany.
¹⁷ Max Planck Laboratory for Structural Biology, Chemistry and Molecular Biophysics of Rosario (MPLbioR, UNR-MPINAT), Partner Laboratory of the Max Planck Institute for Multidisciplinary Sciences (MPINAT, MPG). Centro de Estudios Interdisciplinarios, Universidad Nacional de Rosario, Rosario, Argentina.
¹⁸ Department for NMR-Based Structural Biology, Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany.
¹⁹ Cluster of Excellence "Multiscale Bioimaging: From Molecular Machines to Networks of Excitable Cells," University of Göttingen, Göttingen, Germany.
²⁰ Faculty of Physics, University of Göttingen, Göttingen, Germany.
²¹ Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne, United Kingdom.
²² Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany.

PMID: 40905240
DOI: 10.1002/mds.70030

Abstract

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.

Keywords: Parkinson's disease; genetics; neurodegeneration; protein aggregation; α‐synuclein.

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Update of

A novel alpha-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 AI, Jayanthi V, Amaral L, Agarwal A, Chandran A, Chaves SR, Winkelmann J, Trenkwalder C, Schwager M, Pauli S, Dettmer U, Fernández CO, Lautenschläger J, Zweckstetter M, Busnadiego RF, Mollenhauer B, Outeiro TF. Al-Azzani M, et al. medRxiv [Preprint]. 2025 Feb 14:2025.02.07.25321793. doi: 10.1101/2025.02.07.25321793. medRxiv. 2025. Update in: Mov Disord. 2025 Sep 4. doi: 10.1002/mds.70030. PMID: 39990587 Free PMC article. Updated. Preprint.

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A Novel α-Synuclein K58N Missense Variant in a Patient with Parkinson's Disease

Affiliations

A Novel α-Synuclein K58N Missense Variant in a Patient with Parkinson's Disease

Authors

Affiliations

Abstract

Update of

References

Grants and funding

LinkOut - more resources

Full Text Sources

Miscellaneous