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Targeting the STING-NFκB Pathway via BTK Inhibition: A Dual-Mechanism Therapeutic Strategy Mitigating Neuronal and Microglial Dysfunction in Amyotrophic Lateral Sclerosis [scRNA-seq]

ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder with limited therapeutic interventions. We identified the cGAS-STING-NFκB pathway as a dual therapeutic target that combats both neuronal degeneration and neurotoxic glial activity in ALS. Utilizing SOD1-mutant human iPSC-differentiated motor neurons(hiPSC-MNs) and microglia(hiPSC-MGs), we demonstrated that ALS hiPSC-MGs displayed a pronounced proinflammatory phenotype, characterized by significant inflammatory marker elevation (NLRP3 increased 0.66-fold, secreted IL-1β elevated 2.85-fold compared to controls) and compromised phagocytic capacity (48% reduction in bioparticle uptake). Concurrently, ALS hiPSC-MNs exhibit DNA damage, activating STING-NFκB signaling and triggering caspase-3-mediated apoptosis. Notably, co-culture experiments revealed that inflammatory hiPSC-MGs substantially increased neuronal apoptosis, indicating a toxic intercellular communication mechanism mediated through STING-NFκB signaling. Pharmacological inhibition of Bruton's tyrosine kinase (BTK) - a critical upstream regulator of STING activation - effectively suppressed this inflammatory cascade. This intervention reduced DNA damage in ALS hiPSC-MNs by 61.4% and restored microglial phagocytic function to approximately 87.2% of normal levels. In vivo studies with SOD1-G93A ALS mice demonstrated that BTK inhibitor treatment significantly improved motor performance, extended median survival (183 days versus 158 days in untreated controls), and mitigated neuropathological progression. The treatment enhanced motor neuron survival, reduced microgliosis and astrogliosis, and modulated the PI3K-AKT-mTOR pathway without disrupting autophagy-lysosome dynamics. Our study presents a translational therapeutic strategy that simultaneously addresses neuron-intrinsic and glial-mediated mechanisms in ALS, providing a compelling rationale for repurposing BTK inhibitors in future ALS clinical trials.

ORGANISM(S): Homo sapiens

PROVIDER: GSE299856 | GEO | 2026/06/13

REPOSITORIES: GEO

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Project description:We established iPSCs from healthy donors, SOD1-ALS and TDP43-ALS patients. Using our differentiation protocol originally developed by Reinhardt et al.,2013, we diferentiated these iPSCs toward spinal motor neurons (MNs) and reproduce ALS pathology in a dish. To extend our understanding of finding different molecular mechanisms and pathways related to SOD1- and TDP43 mutations in ALS disease, we have performed a comprehensive gene expression profiling study using RNA-Seq of the iPSC-derived MN models from control individuals and carefully compared with those from SOD1-ALS and TDP43-ALS patients. To generate novel hypotheses of putative underlying molecular mechanisms in ALS, we used human induced pluripotent stem cell (hiPSCs)-derived motor neurons (MNs) from SOD1- and TARDBP (TDP-43 protein)-mutant-ALS patients and healthy controls to perform high-throughput RNA-sequencing (RNA-Seq). An integrated bioinformatics approach was employed to identify differentially expressed genes (DEGs) and key pathways underlying these familial forms of the disease (fALS). In TDP43-ALS, we found dysregulation of transcripts encoding components of the transcriptional machinery and transcripts involved in splicing regulation were particularly affected. In contrast, less is known about the role of SOD1 in RNA metabolism in motor neurons. Here we found that many transcripts relevant for mitochondrial function were specifically altered in SOD1-ALS, indicating transcriptional signatures and expression patterns can vary significantly depending on the causal gene that is mutated. Surprisingly, however, we identified a clear downregulation of genes involved in protein translation in SOD1-ALS suggesting that ALS-causing SOD1 mutations shift cellular RNA abundance profiles to cause neural dysfunction. Altogether, we provided here an extensive profiling of mRNA expression in two ALS models at the cellular level, corroborating the major role of RNA metabolism and protein translation as a common pathomechanism in ALS

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Targeting the STING-NFκB Pathway via BTK Inhibition: A Dual-Mechanism Therapeutic Strategy Mitigating Neuronal and Microglial Dysfunction in Amyotrophic Lateral Sclerosis [scRNA-seq]

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