Synphilin-1 modulates alpha-synuclein assembly, release and uptake
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.
Lázaro, Diana F.
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Amen, Triana
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Gerhardt, Ellen
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Song, Chengyuan
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Burns, Ryan
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Kruse, Niels
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Santos, Patrícia I.
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Milovanovic, Dragomir
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Höglinger, Günter
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Mollenhauer, Brit
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Luk, Kelvin C.
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Lee, Virginia M.Y.
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Outeiro, Tiago F.
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20 November 2025
Lázaro, Diana F.
b61ddb8a-39ba-42ee-a14e-8a70f735441d
Amen, Triana
388dc540-e819-4d07-8f1e-ee0f3949a54b
Gerhardt, Ellen
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Song, Chengyuan
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Burns, Ryan
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Kruse, Niels
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Santos, Patrícia I.
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Milovanovic, Dragomir
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Höglinger, Günter
b737d8cf-4442-4449-a102-817372cb6a21
Mollenhauer, Brit
c70f7374-140b-43e4-acf8-ee0053b9521c
Luk, Kelvin C.
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Lee, Virginia M.Y.
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Outeiro, Tiago F.
7dbde9a9-3c04-491d-aed5-1a4f871830f0
Lázaro, Diana F., Amen, Triana, Gerhardt, Ellen, Song, Chengyuan, Burns, Ryan, Kruse, Niels, Santos, Patrícia I., Milovanovic, Dragomir, Höglinger, Günter, Mollenhauer, Brit, Luk, Kelvin C., Lee, Virginia M.Y. and Outeiro, Tiago F.
(2025)
Synphilin-1 modulates alpha-synuclein assembly, release and uptake.
npj Parkinson's Disease, 11 (1), [326].
(doi:10.1038/s41531-025-01144-3).
Abstract
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.
Text
s41531-025-01144-3
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Accepted/In Press date: 1 September 2025
e-pub ahead of print date: 20 November 2025
Published date: 20 November 2025
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© The Author(s) 2025.
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Local EPrints ID: 511703
URI: http://eprints.soton.ac.uk/id/eprint/511703
ISSN: 2373-8057
PURE UUID: aa411f32-ae55-46ea-99a8-a5c6affda0bd
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Date deposited: 28 May 2026 16:47
Last modified: 29 May 2026 02:09
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Contributors
Author:
Diana F. Lázaro
Author:
Triana Amen
Author:
Ellen Gerhardt
Author:
Chengyuan Song
Author:
Ryan Burns
Author:
Niels Kruse
Author:
Patrícia I. Santos
Author:
Dragomir Milovanovic
Author:
Günter Höglinger
Author:
Brit Mollenhauer
Author:
Kelvin C. Luk
Author:
Virginia M.Y. Lee
Author:
Tiago F. Outeiro
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