Targeted degradation of α-synuclein by arginine-based PROTACs

Parkinson's disease (PD), the second most prevalent neurodegenerative disorder, is associated with α-synuclein (α-syn) overexpression or mutation, leading to harmful aggregates and neuronal apoptosis. Effective drugs that inhibit or reduce α-syn accumulation remain challenging. Targeted protein degradation (TPD) technology offers a novel solution by utilizing the ubiquitin-proteasome pathway to target specific proteins for destruction. Here, we have developed Proteolysis Targeting Chimera (PROTAC) to target α-syn for degradation. Specifically, our PROTACs employ the amino acid arginine (Arg) as the E3 ligase ligand and a benzothiazole-aniline variant as the warhead for α-syn. The efficacy of these PROTACs in degrading α-syn and its aggregates was tested in mammalian cells and Caenorhabditis elegans (C. elegans) models. Arg-PEG1-T^α-syn shows the highest degradation effect in mammalian cells for both wild-type α-syn and the α-syn (A53T) mutant. UBR1 is the ubiquitin E3 ligase responsible for PROTAC-mediated degradation. Furthermore, Arg-PEG1-T^α-syn significantly reduces α-syn aggregates and associated toxicities in both mammalian cells and C. elegans. These findings highlight the potential of a single amino acid-based PROTAC targeting α-syn for degradation, representing a possible therapeutic approach for PD and other synucleinopathies.