Breaking the proteasome balance: α-synuclein and the ubiquitin-proteasome system

Aging is the major risk factor for synucleinopathies, including Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy. However, the molecular mechanisms linking aging to. α-Synuclein cytotoxicity remain incompletely understood. The progressive decline of proteostasis is central among these mechanisms, as the ubiquitin-proteasome system (UPS) and the autophagy-lysosome pathway fail to maintain the turnover of aggregation-prone proteins. In this review, we focus on the bidirectional crosstalk between α-Synuclein and the proteasome as a key driver of proteostasis collapse in synucleinopathies. Proteasome activity declines during aging, and proteasomal dysfunction is closely associated with disease progression. We first discuss how. α-Synuclein structure and posttranslational modifications determine whether the protein is targeted for degradation by the UPS or autophagy or instead acts as a proteolytic inhibitor. Next, the mechanisms by which pathogenic α-synuclein species interact with and impair 20S/26S proteasomes, affecting proteolytic activity, subunit composition, and complex assembly, are discussed. These interactions establish a self-amplifying cycle of proteasome inhibition and α-Synuclein accumulation. As a consequence, the cellular capacity to clear misfolded proteins progressively declines, promoting toxic α-Synuclein aggregation and neurodegeneration. We further discuss the importance of autophagy on α-Synuclein turnover and how this is impaired in synucleinopathies. Finally, we highlight emerging therapeutic strategies aimed at restoring proteasome function and proteostasis. A deeper understanding of how α-Synuclein-proteasome interactions change during ageing may reveal new molecular targets and support the development of disease-modifying therapies for synucleinopathies.