Gomisin N ameliorates autophagy-neuroinflammation imbalance in Parkinson's disease models via modulating the ATG16L1/NLRP3 axis.
Gomisin N ameliorates autophagy-neuroinflammation imbalance in Parkinson's disease models via modulating the ATG16L1/NLRP3 axis.
Where did the research take place?
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Hong Kong, HK · Author affiliation
Mr. & Mrs. Ko Chi-Ming Centre for Parkinson's Disease Research (CPDR), Golden Meditech Centre for NeuroRegeration Science (GCNS), School of Chinese Medicine, Hong Kong Baptist University, Hong Kong Special Administrative Region of China; School of Pharmacy, Henan University of Chinese Medicine, Zhengzhou, 450046, China.Location evidence
Zhengzhou, CN · Author affiliation
School of Pharmacy, Henan University of Chinese Medicine, Zhengzhou, 450046, China.Location evidence
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Original abstract
BACKGROUND: Parkinson's disease (PD) is characterized by dopaminergic neuron loss, α-synuclein accumulation, and sustained neuroinflammation. Autophagy can remove pathogenic α-synuclein and restrain NLR family pyrin domain containing 3 (NLRP3) inflammasome activation. Gomisin N (GN), a lignan from Schisandra chinensis, is neuroprotective, but its mechanism in PD remains incompletely defined. PURPOSE: To determine whether GN protects against PD-like pathology by coordinating autophagy and neuroinflammation through autophagy related 16 like 1 (ATG16L1). METHODS: Neuronal and microglial cell models, as well as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mice with ATG16L1 knockdown, were assessed through pharmacological, behavioral, biochemical, and immunohistochemical analyses. RESULTS: GN crossed the blood-brain barrier, improved motor performance, preserved dopaminergic neurons, reduced α-synuclein oligomers, and suppressed NLRP3/caspase-1/interleukin-1β signaling in MPTP-treated mice. Mechanistically, GN increased the mRNA and protein levels of ATG16L1, enhanced ATG16L1-ATG5 complex formation, and promoted autophagic flux and lysosomal function without canonical mTORC1 inhibition Notably, we uncovered a vicious cycle where α-synuclein overexpression suppressed ATG16L1, impairing autophagy; GN effectively rescued this compromised ATG16L1 expression, facilitating targeted α-synuclein degradation. In microglia, GN blunted NLRP3 inflammasome activation by promoting the ATG16L1-dependent autophagic degradation of essential inflammasome components. Crucially, ATG16L1 knockdown completely abrogated the neuroprotective and anti-inflammatory effects of GN both in vitro and in vivo. CONCLUSION: GN is a brain-penetrant preclinical candidate that links ATG16L1-dependent autophagy with α-synuclein clearance and NLRP3 inflammasome suppression in PD models.