%0 Journal Article
%A Lázaro, Diana F
%A Amen, Triana
%A Gerhardt, Ellen
%A Song, Chengyuan
%A Burns, Ryan
%A Kruse, Niels
%A Santos, Patrícia I
%A Milovanovic, Dragomir
%A Höglinger, Günter
%A Mollenhauer, Brit
%A Luk, Kelvin C
%A Lee, Virginia My-
%A Outeiro, Tiago F
%T Synphilin-1 modulates alpha-synuclein assembly, release and uptake.
%J npj Parkinson's Disease
%V 11
%N 1
%@ 2373-8057
%C [London]
%I Springer Nature
%M DZNE-2025-01297
%P 326
%D 2025
%X 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.
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:41266386
%R 10.1038/s41531-025-01144-3
%U https://pub.dzne.de/record/282474