Targeting the cGAS-STING pathway mitigates Huntington disease pathogenesis in a knock-in mouse model.

Area of Science:

• Neuroimmunology
• Innate Immunity
• Neurodegenerative Diseases

Background:

• The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is crucial for cytosolic DNA sensing and innate immune responses.
• Previous studies indicated cGAS upregulation in cellular models of Huntington's disease (HD), affecting autophagy and inflammation.
• The in vivo role of cGAS in HD pathogenesis remained undetermined.

Purpose of the Study:

• To investigate the in vivo role of the cGAS-STING pathway in Huntington's disease progression.
• To evaluate the therapeutic potential of cGAS-STING pathway inhibition in HD mouse models.

Main Methods:

• Genetic ablation of cGAS in Q175DN knock-in HD mice.
• Longitudinal behavioral assessments (motor function, body weight).
• Histological analyses (ventricle size, glial activation), transcriptomic profiling, and lipidomic analysis of HD brains.
• Pharmacological inhibition of STING using H-151 in HD mice.

Main Results:

• cGAS deletion significantly ameliorated motor deficits and body weight loss in HD mice.
• Histological analysis showed reduced brain atrophy and neuroinflammation (astrogliosis, microgliosis) in cGAS-ablated HD mice.
• Transcriptomic and lipidomic analyses revealed shifts in gene expression and immunoregulatory lipid profiles towards a protective state.
• STING inhibition with H-151 improved motor performance, reduced striatal atrophy, and attenuated glial activation in HD mice.

Conclusions:

• The cGAS-STING pathway is a critical driver of Huntington's disease progression.
• Inhibition of the cGAS-STING pathway represents a promising therapeutic strategy for Huntington's disease.