Cofilin 1-138 Promotes Mitochondrial Dysfunction and Synaptic Degeneration in Parkinson's Disease

Parkinson's disease (PD) is marked by α-synuclein aggregation, mitochondrial dysfunction, and synaptic degeneration, yet the molecular mediators linking these pathological events remain poorly defined. Full-length cofilin (cofilin FL), an actin-binding protein, can be cleaved by asparagine endopeptidase (AEP) to generate the truncated fragment cofilin 1-138, which is known to exert enhanced neurotoxicity in neurodegenerative disorders. However, its role in PD pathogenesis has not been established. In this study, we demonstrate that cofilin 1-138 is elevated in the striatum of PD patients and α-synuclein A53T mice, where it colocalizes with pathological p-S129 α-synuclein. In vitro, cofilin 1-138 exhibited lower phosphorylation levels than full-length cofilin (cofilin FL), suggesting that its activity may be increased. Functionally, cofilin 1-138 promoted neuronal apoptosis, as evidenced by increased Bax and cleaved-caspase-3 expression, enhanced TUNEL positivity, and reduced cell viability. In primary neurons, cofilin 1-138 exacerbated synaptic damage, including reduced synaptic protein expression and neurite degeneration. Moreover, cofilin 1-138 induced mitochondrial dysfunction, characterized by mitochondrial fragmentation, impaired fusion, decreased membrane potential, and reduced ATP production. Collectively, this study demonstrates that cofilin 1-138 is an important pathogenic factor in Parkinson's disease that promotes mitochondrial dysfunction and synaptic degeneration, providing new insights into the molecular mechanisms of PD and potential therapeutic targets.