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

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Abstract 

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 α-synuclein, which accumulates as oligomers or fibrils in Lewy bodies. Although fibrillar forms of α-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 α-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 α-synuclein levels. In this article, we discuss the impact of α-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.

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Acknowledgements

Authors acknowledge the members of P.M. laboratory for their inputs and comments.

Funding

This work is supported by SERB (ECR/2017/003431), MoE-STARS/STARS-1/PID (STARS1/634), and HGK-IYBA (BT/11/IYBA/2018/08) grants to PM. PM duly acknowledges the support of Ramalingaswami Fellowship, Department of Biotechnology, GOI. AAP is a recipient of PMRF, GOI.

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  1. Department of Animal Biology, School of Life Sciences, University of Hyderabad, Hyderabad, 500046, India

    Subhashree Sahoo, Amrita Arpita Padhy, Varsha Kumari & Parul Mishra

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  1. Subhashree Sahoo
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  2. Amrita Arpita Padhy
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S.S., V.K., A.A.P., and P.M. conceptualized, drafted, edited, and reviewed the manuscript.

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Correspondence to Parul Mishra.

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Sahoo, S., Padhy, A.A., Kumari, V. et al. Role of Ubiquitin–Proteasome and Autophagy-Lysosome Pathways in α-Synuclein Aggregate Clearance. Mol Neurobiol 59, 5379–5407 (2022). https://doi.org/10.1007/s12035-022-02897-1

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