Abstract
Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder characterized by the degeneration of spinal motor neurons and muscle atrophy. The disease is mainly caused by low level of the survival motor neuron (SMN) protein, which is coded by two genes, namely SMN1 and SMN2, but leads to selective spinal motor neuron degeneration when SMN1 gene is deleted or mutated. Previous reports have shown that SMN-protein-deficient astrocytes are abnormally abundant in the spinal cords of SMA model mice. However, the mechanism of the SMN- deficient astrocyte abnormality remains unclear. The purpose of this study is to identify the cellular signaling pathways associated with the SMN-deficient astrocyte abnormality and propose a candidate therapy tool that modulates signaling. In the present study, we found that the astrocyte density was increased around the central canal of the spinal cord in a mouse SMA model and we identified the dysregulation of Notch signaling which is a known mechanism that regulates astrocyte differentiation and proliferation, in the spinal cord in both early and late stages of SMA pathogenesis. Moreover, pharmacological inhibition of Notch signaling improved the motor functional deficits in SMA model mice. These findings indicate that dysregulated Notch signaling may be an underlying cause of SMA pathology.
Highlights
Spinal muscular atrophy (SMA) is an autosomal recessive disorder characterized by a loss of motor neurons, leading to skeletal muscle weakness and atrophy[1]
Astrogliosis in the spinal cords of SMNΔ7 mice has been detected as increased glial fibrillary acidic protein (GFAP) immunoreactivity starting from PND59,19,21; the pattern of astrogliosis in SMA has not been studied in depth
To elucidate the site of the astrocytic abnormality at the pathological stage (PND11), we investigated the expression pattern of GFAP in the lumbar spinal cord of SMNΔ7 mice, in which central nervous degeneration caused by ubiquitous SMN depletion preceded gastrocnemius atrophy (Supplemental Fig. 7A–F)
Summary
Spinal muscular atrophy (SMA) is an autosomal recessive disorder characterized by a loss of motor neurons, leading to skeletal muscle weakness and atrophy[1]. Several groups, including ours, have previously shown that glial fibrillary acidic protein (GFAP)- or S100-positive astrocytes are abundant in spinal motor neuron cultures derived from induced pluripotent stem cells (iPSC) obtained from SMA patients (SMA-iPSC MNs)[10,11]. Previous reports have proposed that astrocyte differentiation may be controlled by Notch signaling, a cell communication mechanism involving signal transmission between adjacent cells (juxtacrine signaling) This mechanism suppresses embryonic neurogenesis and promotes astrogenesis immediately after birth[15,16,17,18]. (O) The Quantitative analysis of GFAP-Ki67-positive cell rate in the spinal cord of WT and SMNΔ7 mice at PND5. The up- or down-regulation of Notch signaling was detected in different cell types
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