Single-nucleus multiome shows motor neuron glutamate overactivation in amyotrophic lateral sclerosis

Abstract Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that causes motor neuron degeneration. However, the mechanisms underlying the selective vulnerability of motor neurons and the involvement of non-motor neuron cells in ALS remain unclear. To investigate ALS pathology at the cellular level, we performed a single-nucleus multiome analysis, including RNA sequencing and chromatin accessibility profiling, on motor cortex (75,583 nuclei) and spinal cord (62,711 nuclei) from patients with ALS (n=6) and controls (n=6). Our results revealed significant gene expression changes specifically in spinal motor neurons, including upregulation of a metabotropic glutamate receptor, GRM5, and enhanced glutamate signaling. By integrating genome-wide association study data, we identified ALS-associated SNPs in regulatory regions, suggesting cell-type-specific enrichment of risk, especially in microglia. These findings suggest that changes in spinal motor neurons and their surrounding environment, including glutamate signaling, may be involved in ALS pathology. The study also provides valuable resources for future research on the underlying mechanisms and potential therapeutic targets.