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Updated: Jun 29, 2025
Gene-environment Interaction Models to Unmask Susceptibility Mechanisms in Parkinson's Disease
Published on: January 7, 2014
Pyroptosis-mediator GSDMD promotes Parkinson's disease pathology via microglial activation and dopaminergic neuronal
Xiaoshuang Zhang1, Yunhe Zhang1, Boya Wang1
1Department of Translational Neuroscience, Jing' an District Centre Hospital of Shanghai, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, 138 Yixueyuan Road, Shanghai 200032, China.
Abstract:
GSDMD-mediated pyroptosis occurs in the nigrostriatal pathway in Parkinson's disease animals, yet the role of GSDMD in neuroinflammation and death of dopaminergic neurons in Parkinson's disease remains elusive. Here, our in vivo and in vitro studies demonstrated that GSDMD, as a pyroptosis executor, contributed to glial reaction and death of dopaminergic neurons across different Parkinson's disease models. The ablation of the Gsdmd attenuated Parkinson's disease damage by reducing dopaminergic neuronal death, microglial activation, and detrimental transformation. Disulfiram, an inhibitor blocking GSDMD pore formation, efficiently curtailed pyroptosis, thereby lessening the pathology of Parkinson's disease. Additionally, a modification in GSDMD was identified in the blood of Parkinson's disease patients in contrast to healthy subjects. Therefore, the detected alteration in GSDMD within the blood of Parkinson's disease patients and the protective impact of disulfiram could be promising for the diagnostic and therapeutic approaches against Parkinson's disease.
Insights
Gasdermin D (GSDMD) drives neuroinflammation and dopaminergic neuron death in Parkinson's disease models. Inhibiting GSDMD with disulfiram or its genetic ablation offers therapeutic potential for Parkinson's disease.
Area of Science:
- Neuroscience
- Immunology
- Pathology
Background:
- Pyroptosis, a programmed cell death pathway, is implicated in Parkinson's disease (PD) pathogenesis.
- Gasdermin D (GSDMD) is a key executor of pyroptosis, but its specific role in PD neuroinflammation and dopaminergic neuron loss was unclear.
Purpose of the Study:
- To investigate the role of GSDMD in PD-related neuroinflammation and dopaminergic neuron death.
- To evaluate the therapeutic potential of GSDMD inhibition in PD models.
Main Methods:
- In vivo and in vitro studies using Parkinson's disease models.
- Genetic ablation of Gsdmd.
- Pharmacological inhibition of GSDMD using disulfiram.
- Analysis of dopaminergic neuron survival, microglial activation, and GSDMD modifications in patient blood.
Main Results:
- GSDMD promoted glial activation and dopaminergic neuron death in PD models.
- Gsdmd ablation attenuated PD-associated damage, including reduced neuronal death and microglial activation.
- Disulfiram effectively inhibited pyroptosis and lessened PD pathology.
- A distinct GSDMD modification was observed in the blood of PD patients compared to controls.
Conclusions:
- GSDMD is a critical mediator of neuroinflammation and dopaminergic neuron death in Parkinson's disease.
- GSDMD inhibition, via genetic or pharmacological means (e.g., disulfiram), demonstrates therapeutic promise for PD.
- GSDMD alterations in patient blood may serve as a potential diagnostic biomarker for Parkinson's disease.
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