Dysregulation of Aldh1a2 underlies motor neuron degeneration in spinal muscular atrophy

Lower motor neuron degeneration is the pathological hallmark of spinal muscular atrophy (SMA), a hereditary motor neuron disease caused by loss of the SMN1 gene and the resulting deficiency of ubiquitously expressed SMN protein. The molecular mechanisms underlying motor neuron degeneration, however, remain elusive. To clarify the cell-autonomous defect in developmental processes, we here performed transcriptome analyses of isolated embryonic motor neurons of SMA model mice to explore mechanisms of dysregulation of cell-typespecific gene expression. Of 12 identified genes that were differentially expressed between the SMA and control motor neurons, we focused on Aldh1a2, an essential gene for lower motor neuron development. In primary spinal motor neuron cultures, knockdown of Aldh1a2 led to the formation of axonal spheroids and neurodegeneration, reminiscent of the histopathological changes observed in human and animal cellular models. Conversely, Aldh1a2 rescued these pathological features in spinal motor neurons derived from SMA mouse embryos. Our findings suggest that developmental defects due to Aldh1a2 dysregulation enhances lower motor neuron vulnerability in SMA.

Automated summary

Lower motor neuron degeneration is a pathological feature of spinal muscular atrophy (SMA), a hereditary motor neuron disease caused by loss of the SMN1 gene and resulting deficiency of SMN protein. The molecular mechanisms underlying motor neuron degeneration are still unknown. In this study, transcriptome analysis of isolated embryonic motor neurons from SMA model mice revealed dysregulation of cell-type specific gene expression, with Aldh1a2 identified as a key gene for lower motor neuron development. Knockdown of Aldh1a2 in primary spinal motor neuron cultures led to axonal spheroid formation and neurodegeneration, similar to histopathological changes observed in human and animal models. Conversely, Aldh1a2 rescued these pathological features in SMA mouse embryos. These findings suggest that dysregulation of Aldh1a2 during development enhances lower motor neuron vulnerability in SMA.