Abstract
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.