Neuronal–Glial Communication Perturbations in Murine SOD1G93A Spinal Cord

Amyotrophic lateral sclerosis (ALS) is an incurable disease characterized by proteinaceous aggregate accumulation and neuroinflammation culminating in rapidly progressive lower and upper motor neuron death. To interrogate cell-intrinsic and inter-cell type perturbations in ALS, single-nucleus RNA sequencing was performed on the lumbar spinal cord in the murine ALS model SOD1G93A transgenic and littermate control mice at peri-symptomatic onset stage of disease, age 90 days. This work uncovered perturbed tripartite synapse functions, complement activation and metabolic stress in the affected spinal cord; processes evidenced by cell death and proteolytic stress-associated gene sets. Concomitantly, these pro-damage events in the spinal cord co-existed with dysregulated reparative mechanisms. This work provides a resource of cell-specific niches in the ALS spinal cord and asserts that interwoven dysfunctional neuronal-glial communications mediating neurodegeneration are underway prior to overt disease manifestation and are recapitulated, in part, in the human post-mortem ALS spinal cord. Overall design: Single-nucleus RNA-seq data were generated for three male and three female mice of each B6.Cg-Tg(SOD1*G93A)1Gur/J amyotrophic lateral sclerosis-like and C57BL/6J wild-type control mice, for a total of 12 mice. One replicate of each sex/genotype combination was included in each of three 10X Genomics batches, each sample within a batch containing unique nuclear hashtag oligos to enable demultiplexing in silico.