REVIEW article
Front. Cell. Neurosci.
Sec. Cellular Neuropathology
Dual targeting of the UPS and autophagy as a novel therapy for neurodegenerative proteinopathies.
Provisionally accepted
- Merck Sharp & Dohme Corp (United States), West Point, United States
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Neurodegenerative proteinopathies are characterised by impaired protein clearance and the accumulation of misfolded or aggregated proteins, ultimately leading to neuronal death. The two principal pathways responsible for protein degradation in cells are the ubiquitin proteasome system (UPS) and autophagy. Emerging evidence indicates that these pathways share regulatory components and engage in extensive crosstalk. In this review, we summarise the mechanisms of the UPS and autophagy, highlight their points of interaction, and discuss therapeutic opportunities to modulate both systems in parallel to enhance protein clearance in neurodegenerative disease.
Keywords: Autophagy, Neurodegenearation, Neurodegenerative diseasaes, Proteasome, Therapeutics, UPS - ubiquitin proteasome system
Received: 03 Nov 2025; Accepted: 20 Jan 2026.
Copyright: © 2026 Lines, Helley, Gillotin, Brownlees, Duce and Smethurst. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Georgie Lines
Phillip Smethurst
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