Autophagy-Mediated Targeted Protein Degradation: Mechanisms, Therapeutic Potential, and Future Directions

Spa, Léon (2025) Autophagy-Mediated Targeted Protein Degradation: Mechanisms, Therapeutic Potential, and Future Directions. Bachelor's Thesis, Biology.

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Abstract

Over the last decades, targeted protein degradation (TPD) has gained attention as a promising therapeutic strategy. However, proteasome-dependent technologies like PROTACs are largely restricted to soluble proteins within the cytosol. In contrast, autophagy-mediated TPD technologies, such as AUTOTACs, AUTACs, ATTECs and LYTACs expand the degradable targets to include aggregated proteins, organelles and membrane or extracellular proteins. This review aims to offer a comparative analysis of lysosome-targeting strategies, highlighting their distinct mechanisms of action. These include p62–mediated clearance of protein aggregates (AUTOTACs), K63 ubiquitin tagging (AUTACs), ATG8-based cargo tethering (ATTECs) and receptor-mediated lysosomal trafficking (LYTACs). These technologies are showing promising results in degrading disease-relevant substrates such as α-synuclein, mutant tau, huntingtin, lipid droplets, and PD-L1 in preclinical models. Despite the promising potential of these degraders, several major challenges remain. Many exhibit poor solubility, limited cellular or BBB permeability and often rely on stoichiometric action rather than catalytic action. Additionally, receptor recycling bottlenecks (e.g., in LYTACs) and impaired autophagy mechanisms in target diseases (e.g., in Parkinson’s Disease) may reduce efficacy. Delivery innovations such as nanocarriers and receptor-mediated transcytosis are actively being explored to overcome these barriers.

Item Type:	Thesis (Bachelor's Thesis)
Supervisor name:	Mauthe, M.
Degree programme:	Biology
Thesis type:	Bachelor's Thesis
Language:	English
Date Deposited:	02 Jul 2025 13:59
Last Modified:	02 Jul 2025 13:59
URI:	https://fse.studenttheses.ub.rug.nl/id/eprint/35768

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