HAN, Y. | Search bioRxiv

bioRxiv2025

Microglial GSDMD-Mediated Pyroptosis Drives Neuroinflammation in Parkinson's Disease

RationaleParkinsons disease (PD), a globally prevalent neurodegenerative disorder, is characterized by substantia nigra dopaminergic neuron degeneration and striatal dopamine depletion. While microglial pyroptosis is implicated in neuroinflammation and neural injury via inflammatory cytokine release, the role of the CASPASE-1/GSDMD pathway in PD pathogenesis remains incompletely defined. Methods1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was used to construct PD model in vivo, GSDMD-knockout mice was employed to assess pyroptotic mechanisms. MPP-stimulated BV2 microglia were treated with a CASPASE-1 inhibitor in vitro. Microglia-specific GSDMD conditional knockout mice were generated to evaluate cell-type contributions to neuroinflammation and motor deficits. ResultsGSDMD deficiency attenuated MPTP-induced neuroinflammation, dopaminergic neuron loss, and motor dysfunction in vivo. MPP exposure triggered NLRP3 inflammasome activation and pyroptosis in BV2 microglia, which was suppressed by CASPASE-1 inhibition. Critically, microglia-specific GSDMD ablation mitigated nigrostriatal degeneration and dyskinesia in PD mice, confirming the centrality of microglial pyroptosis. ConclusionOur findings demonstrate that microglia drive neuroinflammation in PD via CASPASE-1/GSDMD-mediated pyroptosis, directly linking this pathway to dopaminergic neurodegeneration and motor impairment. Targeting GSDMD-dependent pyroptosis represents a promising therapeutic strategy.

neuroscience↗

bioRxiv2024

Reversal of Obesity by Enhancing Slow-wave Sleep via a Prokineticin Receptor Neural Circuit

Obese subjects often exhibit hypersomnia accompanied by severe sleep fragmentation, while emerging evidence suggests that poor sleep quality promotes overeating and exacerbates diet-induced obesity (DIO). However, the neural circuit and signaling mechanism underlying the reciprocal control of appetite and sleep is yet not elucidated. Here, we report a neural circuit where prokineticin receptor 2 (PROKR2)-expressing neurons within the parabrachial nucleus (PBN) of the brainstem received direct projections from neuropeptide Y receptor Y2 (NPY2R)-expressing neurons within the lateral preoptic area (LPO) of the hypothalamus. The RNA-Seq results revealed Prokr2 in the PBN is the most regulated GPCR signaling gene that is responsible for comorbidity of obesity and sleep dysfunction. Furthermore, those NPY2RLPO neurons are minimally active during NREM sleep and maximally active during wakefulness and REM sleep. Activation of the NPY2RLPO[->]PBN circuit or the postsynaptic PROKR2PBN neurons suppressed feeding of a high-fat diet and abrogated morbid sleep patterns in DIO mice. Further studies showed that genetic ablation of the PROKR2 signaling within PROKR2PBN neurons alleviated the hyperphagia and weight gain, and restored sleep dysfunction in DIO mice. We further discovered pterostilbene, a plant-derived stilbenoid, is a powerful anti-obesity and sleep-improving agent, robustly suppressed hyperphagia and promoted reconstruction of a healthier sleep architecture, thereby leading to significant weight loss. Collectively, our results unveil a neural mechanism for the reciprocal control of appetite and sleep, through which pterostilbene, along with a class of similarly structured compounds, may be developed as effective therapeutics for tackling obesity and sleep disorders.

neuroscience↗