c-Cbl overexpression alleviates pathological damage in Parkinson's disease by suppressing NLRP3 inflammasome-mediated neuroinflammation via the NF-κB signaling pathway.

Abstract

Parkinson's disease (PD), the world's second most prevalent neurodegenerative disorder, is characterized by midbrain substantia nigra dopaminergic (DA) neuron loss, neuroinflammation, and α-synuclein aggregation. c-Cbl, a RING-finger E3 ubiquitin ligase highly expressed in the substantia nigra and striatum, regulates neuroinflammation via the NF-κB pathway. Prior studies showed that reduced c-Cbl expression triggers microglia-mediated neuroinflammation in LPS- and MPTP-induced PD models, but whether c-Cbl overexpression suppresses NLRP3 inflammasome activation to alleviate PD-related neuroinflammation remains unclear. We established LPS-induced chronic neuroinflammatory and Parkin-deficient PD models, confirming downregulated c-Cbl expression. In vitro, LV-c-Cbl overexpression in PC12 cells mitigated NLRP3 activation, autophagy dysfunction, and DA neuron loss. In vivo, stereotaxic AAV-c-Cbl injection in LPS model mice and Parkin+/- mice inhibits NLRP3 inflammasome activation via the NF-κB signaling pathway, autophagic impairment, DA neuron damage, and motor dysfunction. Collectively, c-Cbl is a promising therapeutic target for PD.