Cellular and systemic modifiers of alpha-synuclein proteostasis

Ageing is a primary risk factor for neurodegenerative disorders, including Parkinson's disease (PD). As individuals age, their cells become less efficient in maintaining protein homeostasis, leading to an increased likelihood of protein misfolding and aggregation. A hallmark of PD and other synucleinopathies is the accumulation of alpha-synuclein protein aggregates in affected neurons, a process that is exacerbated by ageing. While cellular mechanisms that regulate protein aggregation have been a primary focus of research, recent studies suggest that other, systemic age-related mechanisms may contribute to alpha-synuclein toxicity. Understanding these alternative pathways is crucial for the development of effective therapeutic strategies to combat neurodegenerative diseases, such as PD. In this review, we synthesize current insights into the biological mechanisms underlying alpha-synuclein toxicity at the organismal level. We highlight key open questions and discuss how these findings may inform the development of targeted interventions to prevent or delay age-related synucleinopathies. This article is part of the Theo Murphy meeting issue 'ProteostaSys: a systems view of proteostasis'.