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

Authors

Chunxiao Bai, Xiaochuan Qi, Anheng Zhu, Ao Wang, Qiaodengke Zhu, Chunjing Wang, Gaofeng Liu, Changqing Liu, Yu Guo

Published in

Biochimica et biophysica acta. Molecular basis of disease. Pages 168450. Sep 05, 2026. Epub Sep 05, 2026.

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.

PMID:
42700873
Bibliographic data and abstract were imported from PubMed on 06 Sep 2026.

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