STING orchestrates the neuronal inflammatory stress response in multiple sclerosis

Area of Science:

• Neuroscience
• Immunology
• Cell Biology

Background:

• Neuroinflammation is a key driver of neurodegeneration in multiple sclerosis (MS).
• The precise molecular mechanisms linking inflammation to neuronal death in MS are not fully understood.
• Neuronal stress responses play a critical role in the pathogenesis of neurodegenerative diseases.

Purpose of the Study:

• To investigate the role of the stimulator of interferon genes (STING) pathway in inflammation-induced neurodegeneration in MS.
• To elucidate the signaling cascade involving STING, glutamate excitotoxicity, and ferroptosis in neurons.
• To identify STING as a potential therapeutic target for mitigating neurodegeneration in MS.

Main Methods:

• Analysis of neuronal inflammatory stress response in MS patients and a mouse model.
• Investigating the interaction between STING and stromal interaction molecule 1 (STIM1).
• Utilizing genetic and pharmacological interventions to modulate STING activity in neurons.

Main Results:

• Neurons in MS and its model induce STING activation.
• Glutamate excitotoxicity triggers STING detachment from STIM1, initiating non-canonical STING signaling.
• This signaling leads to autophagic degradation of glutathione peroxidase 4 (GPX4), inducing ferroptosis and neuronal death.

Conclusions:

• STING is a central regulator of detrimental neuronal inflammatory stress, integrating inflammation and glutamate signaling.
• Targeting neuronal STING, through genetic or pharmacological means, protects against inflammation-induced neurodegeneration.
• STING represents a promising therapeutic target for neurodegenerative diseases like MS.