# Microglial HVCN1 Deficiency Improves Movement and Survival of SOD1G93A ALS Mice by Enhancing Microglial Migration and Neuroprotection

## TL;DR

Deleting HVCN1 in microglia improves motor function and survival in ALS mice by enhancing microglial migration and neuroprotection.

## Contribution

Identifies HVCN1 as a novel, druggable target for ALS therapy through microglial modulation.

## Key findings

- HVCN1 deletion in microglia improves motor neuron survival and neuromuscular junction integrity in ALS mice.
- HVCN1 deficiency suppresses Akt signaling, enhancing microglial migration and neurotrophic functions.
- HVCN1 ablation leads to better motor function and survival in ALS mice compared to current clinical drugs.

## 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 SOD1G93A
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.

Hydrogen voltage gated channel 1 (HVCN1) is upregulated in microglia of both ALS patients and its mouse model. HVCN1 deficiency enhances microglial migration via suppressing Akt signaling, promotes neurotrophic capacity and motor function, and prolongs survival of the SOD1G93A
ALS mice. This study identifies HVCN1 as a novel, promising druggable target for ALS therapy.