Unlocking mitophagy activation with small molecule Targeted Protein Stabilisers

Activation of mitophagy signalling is an emerging therapeutic concept in Parkinson's disease, supported by mutations in upstream components (e.g. PINK1/Parkin) in patient sub-groups. We will develop novel methodology to discover molecules that stabilise a master regulator of mitophagy and boost signalling. This will deliver two transformative advances: 1. Provide specific chemical tools that can validate pharmacological activation of mitophagy in cells and in vivo as a therapeutic concept to treat Parkinson's disease and 2. Validate new methodology that can be readily transferred to other concepts reliant on effecting target protein stability. We will use the concept of inducing proximity of proteins with small molecules to achieve targeted protein stabilisation (TPS). Induced proximity methods have been used with success for targeted protein degradation (TPD), but TPS offers a unique strategy for directly restoring downregulated biological pathways. Despite the potential benefits, TPS methodology is currently limited and has not been applied in the context of rescuing neuronal function. Firstly, a chemical genetics approach will be developed to validate target proteins that activate mitophagy in neurons when stabilised. We will then aim to discover targeted protein stabilisers that can demonstrate selective mitophagy activation in vivo and that penetrate the blood brain barrier.