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.
Cheng-Fu Su, Zhi-Qiang Deng, Ka-Yee Ying et al.· Phytomedicine· 0 citations
BACKGROUND
Microglia, the resident immune cells of the central nervous system (CNS), maintain brain homeostasis and respond to pathological insults. Microglial dysfunction has been implicated in the pathogenesis of several neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and multiple sclerosis. Impaired lysosomal function, particularly defective lysosomal acidification, leads to the accumulation of undegraded material, thereby promoting neuroinflammation and neuronal damage.
PURPOSE
This review examines the mechanisms governing lysosomal acidification in microglia and evaluates its potential as both a therapeutic target and a prognostic biomarker in neurodegenerative diseases.
METHODS
The literature on microglial lysosomal acidification, lysosomal pH regulation, autophagy, and neurodegeneration was searched in PubMed, Scopus, and Web of Science. Relevant mechanistic, preclinical, and translational studies were critically appraised and synthesized.
RESULTS
Lysosomal acidification is increasingly recognized as a key regulator of microglial function and homeostasis. Defective acidification, driven by dysregulation of the vacuolar H+-ATPase (V-ATPase) proton pump, TFEB/TFE3 signaling pathways, and lysosomal ion channels such as TRPML1 and TMEM175, impairs autophagic flux and substrate degradation, facilitating the accumulation of neurotoxic aggregates including amyloid-β and α-synuclein. Emerging evidence suggests that the degree of microglial lysosomal acidification may serve as a prognostic biomarker for disease progression and therapeutic response. Restoration or enhancement of lysosomal acidification through pharmacological modulation of lysosomal pH, activation of autophagy, or targeting of key regulatory pathways has been shown to re-establish microglial homeostasis, attenuate neuroinflammation, and confer neuroprotection in preclinical models.
CONCLUSION
Restoration of microglial lysosomal acidification represents a promising therapeutic strategy for neurodegenerative diseases. A deeper understanding of the molecular mechanisms regulating lysosomal acidification in microglia may facilitate the identification of novel biomarkers and therapeutic targets, ultimately contributing to the development of innovative interventions for neurodegenerative disorders.
R. Jaganathan, Srilakshmi Vijayakumar, Yinchi Chen et al.· Neurobiology of Disease· 0 citations
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