The Mechanism of the Parkin-CMA-NLRP3-PANoptosis Signaling Axis in Parkinson's Disease: From Molecular Basis to Therapeutic Strategies.

Authors

Xinghua Tian, Biao Zhang, Yu Wang, Jianshe Wei

Published in

Progress in neurobiology. Pages 102961. Oct 12, 2026. Epub Oct 12, 2026.

Abstract

Parkinson's Disease (PD) is a common neurodegenerative disorder. Existing clinical interventions merely relieve symptoms and cannot reverse progressive neuronal injury. Neuroinflammation and dysregulated programmed cell death are central pathological drivers of PD. PANoptosis is an integrated pan-programmed cell death, can simultaneously trigger apoptosis, pyroptosis and necroptosis, with the NOD‑like receptor family pyrin domain‑containing 3 (NLRP3) inflammasome serving as a core molecular hub for PANoptosis initiation. Apart from its well‑characterized role in mitophagy, Parkin directly interacts with NLRP3 and mediates K63‑linked ubiquitination at the NLRP3‑K353 residue. This post‑translational modification targets NLRP3 for degradation through chaperone‑mediated autophagy (CMA), which suppresses excessive PANoptosis and preserves dopaminergic neuron survival. This review systematically delineates the molecular framework of the Parkin‑CMA‑NLRP3‑PANoptosis signaling axis. We further discuss its functional crosstalk with canonical PD‑associated pathological events, including α‑synuclein (α‑syn) aggregation and mitochondrial dysfunction, and summarize translational progress of small‑molecule compounds and gene therapies targeting individual components within this cascade. Critical bottlenecks are also addressed, such as unresolved molecular regulatory details, limitations of preclinical animal models, poor blood‑brain barrier permeability of candidate agents, and obstacles for early therapeutic intervention. This work intends to uncover promising targets for PD disease‑modifying treatments and support the advancement of precision therapeutic strategies.

PMID:
42863692
Bibliographic data and abstract were imported from PubMed on 13 Oct 2026.

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