Synphilin-1 modulates alpha-synuclein assembly, release and uptake
Alpha-synuclein (aSyn) is an intrinsically disordered protein involved in phase separation and several age-associated neurodegenerative disorders, including Parkinson's disease. However, its function and pathological role remain elusive. Here, we modeled different aSyn assemblies in living cells by exploiting its interaction with synphilin-1 (Sph1). We developed a model that reports on gel- and solid-like inclusions through coexpression of aSyn and Sph1. Distinct morphological differences emerged between VN-aSyn + aSyn-VC and VN-Sph1 + aSyn-VC assemblies, showing unique antibody recognition, proteinase K resistance, and protein mobilities. The VN-Sph1 + aSyn-VC interaction could be manipulated to alter inclusion size and number. These inclusions also contained lysosomes and AP-1 vesicles, aligning with observations in human brain tissue. Our study offers new insight into aSyn aggregation and release, highlighting the importance of Sph1 and other aSyn-interacting proteins in synucleinopathies, which involve diverse copathologies only now beginning to be understood.
Authors
- Niels Kruse (ORCID: https://orcid.org/0000-0002-4036-8999)
- Ryan D. Burns (ORCID: https://orcid.org/0000-0002-5933-4633)
- Kelvin C. Luk (ORCID: https://orcid.org/0000-0002-6591-6269)
- Diana F. Lázaro (ORCID: https://orcid.org/0000-0001-5593-0342)
- Dragomir Milovanović (ORCID: https://orcid.org/0000-0002-6625-1879)
- Ellen Gerhardt (ORCID: https://orcid.org/0000-0003-1348-8095)
- Tiago F. Outeiro
- Günter U. Höglinger (ORCID: https://orcid.org/0000-0001-7587-6187)
- Triana Amen (ORCID: https://orcid.org/0000-0003-4808-7806)
- Patrícia I. Santos (ORCID: https://orcid.org/0000-0003-1692-3259)
- Brit Mollenhauer (ORCID: https://orcid.org/0000-0001-8437-3645)
- Chengyuan Song (ORCID: https://orcid.org/0000-0003-3314-0635)
- V. M.-Y. Lee
Institutions
- German Center for Neurodegenerative Diseases (DE)
- LMU Klinikum (DE)
- Humboldt-Universität zu Berlin (DE)
- Institute for Neurodegenerative Disorders (US)
- Munich Cluster for Systems Neurology (DE)
- Universitätsmedizin Göttingen (DE)
- Paracelsus Elena Klinik Kassel (DE)
- Institute on Aging (US)
- Max Planck Institute of Experimental Medicine (DE)
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin (DE)
- University of Southampton (GB)
- Max Planck Institute for Multidisciplinary Sciences (DE)
- École Polytechnique Fédérale de Lausanne (CH)
- Freie Universität Berlin (DE)
- Charité - Universitätsmedizin Berlin (DE)
- University of Pennsylvania (US)
- Ludwig-Maximilians-Universität München (DE)
- Newcastle University (GB)
Publication Details
- Journal
- npj Parkinson s Disease
- Published
- 2025-11-20
- DOI
- https://doi.org/10.1038/s41531-025-01144-3
- Primary Topic
- Parkinson's Disease Mechanisms and Treatments
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- EU Joint Programme – Neurodegenerative Disease Research
- Deutsche Forschungsgemeinschaft
- Bundesministerium für Bildung und Forschung