Single-cell RNA sequencing reveals dysregulation of spinal cord cell types in a severe spinal muscular atrophy mouse model

Abstract

Although spinal muscular atrophy (SMA) is a motor neuron disease caused by the loss of survival of motor neuron (SMN) proteins, there is growing evidence that non-neuronal cells play important roles in SMA pathogenesis. However, transcriptome alterations occurring at the single-cell level in SMA spinal cord remain unknown, preventing us from fully comprehending the role of specific cells. Here, we performed single-cell RNA sequencing of the spinal cord of a severe SMA mouse model, and identified ten cell types as well as their differentially expressed genes. Using CellChat, we found that cellular communication between different cell types in the spinal cord of SMA mice was significantly reduced. A dimensionality reduction analysis revealed 29 cell subtypes and their differentially expressed gene. A subpopulation of vascular fibroblasts showed the most significant change in the SMA spinal cord at the single-cell level. This subpopulation was drastically reduced, possibly causing vascular defects and resulting in widespread protein synthesis and energy metabolism reductions in SMA mice. This study reveals for the first time a single-cell atlas of the spinal cord of mice with severe SMA, and sheds new light on the pathogenesis of SMA.

Author summary

Spinal muscular atrophy (SMA) is a neurodegenerative disease caused by functional loss of the SMN protein. Although SMA is characterized by degeneration of motor neurons in the anterior horn of the spinal cord, there is growing evidence that non-neuronal cells play important roles in SMA pathogenesis. It has long been unclear whether and to what extent individual cell types in the SMA spinal cord are affected by the deficiency of the SMN protein. Here, we sequenced the spinal cord of a mouse model of severe SMA using single-cell RNA sequencing. Over 20,000 cells, 10 cell types, 29 subtypes and their differentially expressed genes were identified. Overall, cell-cell communication in SMA is substantially reduced. A subpopulation of vasculature fibroblasts showed the most significant change in the SMA spinal cord at the single-cell level. This reduction may account for the vascular defects and reduced oxygen delivery capacity in SMA mice, as well as the widespread reduction of protein synthesis and energy metabolism in various spinal cell types. These findings not only create the first single-cell omics database for SMA, but also help reveal new pathological mechanisms associated with the disease.