Authors
Lázaro DF, Amen T, Gerhardt E, Song C, Burns R, Kruse N, Santos PI, Milovanovic D, Höglinger G, Mollenhauer B, Luk KC, Lee VM, Outeiro TF
Journal
NPJ Parkinsons Disease
Citation
NPJ Parkinsons Dis. 2025 Nov 20;11(1):326.
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.
