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.

The SMN-ribosome interplay: a new opportunity for Spinal Muscular Atrophy therapies

“…A recent single-cell RNA-seq analysis of the spinal cord of a mouse model of SMA revealed the down-regulation of the genes enriched in ribobiogenesis and translation in oligodendrocytes [ 76 ]. In line with this finding, the treatment of patient fibroblasts with the small molecule Risdiplam up-regulates genes involved in translation-related processes such as ribosome and ribobiogenesis [ 77 ].…”