Natural compound X attenuates astrocytes-mediated neurotoxicity through NF-κB pathway in multiple preclinical ALS/FTD models

초록

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative disorders characterized by astrocyte-mediated neurotoxicity driven by FUS or TDP-43 proteinopathies. However, therapeutic strategies targeting this astrocyte-mediated pathology remain limited. Here, we identified the therapeutic potential of Compound X, a blood–brain barrier penetrant agent with anti-inflammatory properties, in cellular and Drosophila models of FUS P525L- or TDP-43-induced pathology. Compound X modulated NF-κB signaling, suppressed the secretion of proinflammatory cytokines, and reduced the mislocalization and aggregation of FUS and TDP-43 proteins in astrocytes overexpressing FUS P525L or TDP-43. Compound X also alleviated neuronal toxicity and mitochondrial dysfunction induced by these astrocytes. In Drosophila models, Compound X ameliorated locomotor deficits and extended lifespan caused by glial expression of mutant FUS or TDP-43. We further confirmed its therapeutic effect in FUS-ALS patient-derived fibroblasts. Consistently, inflammatory cytokine and chemokine levels induced by FUS P525L or TDP-43 in mouse primary astrocytes were similarly increased in ALS patient plasma, supporting the clinical relevance of our findings. Taken together, these results demonstrate that Compound X targets neuroinflammation and mitochondrial dysfunction, highlighting its translational potential as a therapeutic candidate for ALS/FTD.