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

Parkinson's disease (PD), the most prevalent neurodegenerative movement disorder, is characterized by the progressive loss of dopaminergic (DA) neurons and the accumulation of α-synuclein (αSyn)-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 αSyn toxicity, and growing evidence suggests that αSyn-mitochondrial interactions contribute to PD progression. Our recent findings identify mitochondrial protease ClpP as a crucial regulator of αSyn pathology, with pathological αSyn 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-β component (NAC) domain of αSyn, preventing its association with ClpP. CS2 treatment effectively mitigated αSyn toxicity in an αSyn-stable neuronal cell line, primary cortical neurons inoculated with αSyn 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 αSyn aggregation and neuropathology. These findings establish the ClpP-αSyn interaction as a druggable target in PD and position CS2 as a promising therapeutic candidate for PD and other αSyn-associated neurodegenerative disorders.