Targeting the ClpP-αSynuclein Interaction with a Decoy Peptide to Mitigate Neuropathology in Parkinson's Disease Models

Parkinsons disease (PD), the most prevalent neurodegenerative movement disorder, is characterized by the progressive loss of dopaminergic (DA) neurons and the accumulation of -synuclein (Syn)-rich inclusions. Despite advances in understanding PD pathophysiology, disease-modifying therapies remain elusive, underscoring gaps in our knowledge of its underlying mechanisms. Mitochondria are key targets of Syn toxicity, and growing evidence suggests that Syn-mitochondrial interactions contribute to PD progression. Our recent findings identify mitochondrial protease ClpP as a crucial regulator of Syn pathology, with pathological Syn binding to and impairing ClpP function, thereby exacerbating mitochondrial impairment and neurodegeneration. To disrupt this deleterious interaction, we developed a decoy peptide, CS2, which directly binds to the non-amyloid-{beta} component (NAC) domain of Syn, preventing its association with ClpP. CS2 treatment effectively mitigated Syn toxicity in an Syn-stable neuronal cell line, primary cortical neurons inoculated with Syn pre-formed fibrils (PFFs), and DA neurons derived from PD patient-induced pluripotent stem cells (iPSCs). Notably, subcutaneous administration of CS2 in transgenic mThy1-hSNCA PD mice rescued cognitive and motor deficits while reducing Syn aggregation and neuropathology. These findings establish the ClpP-Syn interaction as a druggable target in PD and position CS2 as a promising therapeutic candidate for PD and other Syn-associated neurodegenerative disorders.