A deep dive into the liquid droplet state of α-synuclein

Abstract

Parkinson's disease (PD) is characterised by the presence of Lewy bodies, aggregates primarily composed of misfolded α-synuclein. Despite extensive research, the precise relationship between α-synuclein aggregation and Lewy body formation remains elusive. This study investigates the dynamic process of α-synuclein aggregation, shedding light on its transition from liquid droplets/condensates to amyloid-rich hydrogels reminiscent of Lewy bodies. Utilising both in vitro assays and a Caenorhabditis elegans model of PD, we elucidate the influence of cellular components on the maturation of α-synuclein condensates into amyloid states. Our findings suggest that factors within the cellular milieu may modulate the kinetics of α-synuclein aggregation, potentially impacting Lewy body pathogenesis. Furthermore, we delve into the microscopic mechanisms underlying α-synuclein aggregation within liquid condensates through fluorescence-based assays. By quantifying spontaneous nucleation and aggregate proliferation kinetics under physiological conditions, we provide insights into the dynamic nature of α-synuclein aggregation. Leveraging this understanding, we explore the efficacy of claramine, a small molecule, in inhibiting α-synuclein condensation and aggregation both in vitro and in vivo. Our results demonstrate the potential of claramine as a therapeutic candidate for PD, highlighting its ability to modulate α-synuclein aggregation pathways. By unravelling the intricacies of α-synuclein dynamics within liquid condensates, this study offers insights into PD pathology and therapeutic interventions. The elucidation of aggregation mechanisms and the identification of potential drug targets underscore the importance of understanding α-synuclein behaviour in diverse biological environments. Ultimately, this research contributes to the development of targeted therapies for PD and related synucleinopathies, addressing a critical need in neurodegenerative disease research.