?-Synuclein-CHMP2B interaction disruptor.

PDpep1.3 is a peptide optimised from a hit from a high-throughput screen to identify protein-protein interaction inhibitors that reduce ?-synuclein oligomer levels and their associated cytotoxicity. PDpep1.3 disrupts the direct interaction between the C-terminal region of ?-synuclein and CHarged Multivesicular body Protein 2B (CHMP2B), a component of the endosomal sorting complex required for transport-III (ESCRT-III). ?-Synuclein impedes endolysosomal activity via this interaction with CHMP2B, inhibiting its own degradation, and blockade of it with PDpep1.3 restores endolysosomal function and decreases ?-synuclein levels in human cells. In vivo, PDpep1.3 protects dopaminergic neurons from ?-synuclein-mediated degeneration in Parkinson’s disease models in rats.

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