cGAS inhibition delays TDP-43-driven ALS Pathogenesis

Area of Science:

• Neuroscience
• Immunology
• Genetics

Background:

• Amyotrophic Lateral Sclerosis (ALS) involves motor neuron degeneration and mislocalization of TAR DNA-binding protein 43 (TDP-43).
• Upstream regulators of TDP-43 pathology and associated RNA splicing defects in ALS remain largely unknown.

Purpose of the Study:

• To identify upstream modulators of TDP-43 pathology in ALS.
• To investigate the role of cyclic GMP-AMP synthase (cGAS) in ALS pathogenesis.
• To evaluate cGAS inhibition as a therapeutic strategy for ALS.

Main Methods:

• Analysis of cGAS expression in ALS patient brains and iPSC-derived microglia-motor neuron co-cultures.
• Pharmacological inhibition of cGAS in vitro and in vivo (TDP-43 Q331K mice).
• Assessment of TDP-43 pathology, RNA splicing, microglial activation, and motor function.

Main Results:

• cGAS expression is elevated in ALS brains and activated microglia.
• Neuronal TDP-43 pathology activates microglial cGAS.
• cGAS inhibition reduced TDP-43 phosphorylation, normalized microglial function, reversed RNA splicing defects, attenuated neurodegeneration, and preserved motor function in mice.

Conclusions:

• cGAS is a key mediator linking innate immune signaling to TDP-43 mis-splicing and neurodegeneration in ALS.
• cGAS is a druggable target for ALS therapy.
• cGAS inhibition represents a promising therapeutic strategy for Amyotrophic Lateral Sclerosis.