Role of Ubiquitin-Proteasome and Autophagy-Lysosome Pathways in α-Synuclein Aggregate Clearance

Synuclein aggregation in neuronal cells is the primary underlying cause of synucleinopathies. Changes in gene expression patterns, structural modifications, and altered interactions with other cellular proteins often trigger aggregation of alpha-synuclein, which accumulates as oligomers or fibrils in Lewy bodies. Although fibrillar forms of alpha-synuclein are primarily considered pathological, recent studies have revealed that even the intermediate states of aggregates are neurotoxic, complicating the development of therapeutic interventions. Autophagy and ubiquitin-proteasome pathways play a significant role in maintaining the soluble levels of alpha-synuclein inside cells; however, the heterogeneous nature of the aggregates presents a significant bottleneck to its degradation by these cellular pathways. With studies focused on identifying the proteins that modulate synuclein aggregation and clearance, detailed mechanistic insights are emerging about the individual and synergistic effects of these degradation pathways in regulating soluble alpha-synuclein levels. In this article, we discuss the impact of alpha-synuclein aggregation on autophagy-lysosome and ubiquitin-proteasome pathways and the therapeutic strategies that target various aspects of synuclein aggregation or degradation via these pathways. Additionally, we also highlight the natural and synthetic compounds that have shown promise in alleviating the cellular damage caused due to synuclein aggregation.