cGAS inhibition delays TDP-43-driven ALS Pathogenesis - PubMed
2 days ago
- #TDP-43
- #ALS
- #cGAS inhibition
- Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by motor neuron loss and TDP-43 mislocalization.
- Cyclic GMP-AMP synthase (cGAS) was identified as a key mediator of TDP-43 pathology and RNA splicing defects in ALS.
- cGAS expression was elevated in ALS patient brains and enriched in activated microglia.
- Pharmacological inhibition of cGAS reduced phosphorylated TDP-43, restored lysosomal and phagocytic functions, and normalized microglial reactivity.
- In vivo studies showed cGAS inhibition reversed RNA splicing abnormalities, attenuated neurodegeneration, and preserved motor function in TDP-43 Q331K mice.
- cGAS inhibition presents a promising therapeutic strategy for ALS by targeting innate immune signaling linked to TDP-43 pathology.