Microglial HVCN1 Deficiency Improves Movement and Survival of SOD1 ^G93A ALS Mice by Enhancing Microglial Migration and Neuroprotection

ABSTRACT Amyotrophic lateral sclerosis (ALS) is an incurable motor neuron disease characterized by progressive loss of motor neurons. Current clinically available drugs targeting neurons show minor survival extension and no motor improvement in ALS patients. This shifts the focus of ALS research toward non‐neuronal cells, particularly microglia, a critical driver of ALS pathogenesis. Highly druggable ion channels are key regulators of microglia function. Here, Hydrogen voltage gated channel 1 (HVCN1) was screened out as the most highly expressed ion channel in microglia, and was upregulated in microglia of SOD1 ^G93A mice and patients. Deletion of HVCN1 in microglia increased motor neuron survival, rescued the innervated neuromuscular junctions in the muscle, reduced glial activation and decreased the level of both misfolded protein and myelin debris in the ALS mice. Importantly, these pathological improvements were translated into significant motor improvement and survival extension in the ALS mice, exhibiting better effects than the current clinical drugs. HVCN1 deletion enhanced microglia migration and their homeostatic state with elevated neurotrophic functions. Mechanistically, HVCN1 ablation promoted microglial migration via suppressing Akt signaling. Our results identify HVCN1 as a novel promising therapeutic target for ALS, opening a new avenue to further develop specific inhibitors for HVCN1 to alleviates ALS.