Notch Signaling Mediates Astrocyte Abnormality in Spinal Muscular Atrophy Model Systems
Notch Signaling Mediates Astrocyte Abnormality in Spinal Muscular Atrophy Model Systems
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DOI：
10.1038/s41598-019-39788-w
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发表时间：
2019-03
影响因子：
4.6
通讯作者：
Kazuki Ohuchi;M. Funato;Y. Yoshino;Shiori Ando;Satoshi Inagaki;Arisu Sato;Chizuru Kawase;Junko Seki;Toshio Saito;H. Nishio;Shinsuke Nakamura;M. Shimazawa;Hideo Kaneko;H. Hara
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文献类型：
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作者：
Kazuki Ohuchi;M. Funato;Y. Yoshino;Shiori Ando;Satoshi Inagaki;Arisu Sato;Chizuru Kawase;Junko Seki;Toshio Saito;H. Nishio;Shinsuke Nakamura;M. Shimazawa;Hideo Kaneko;H. Hara
脊髓性肌萎缩症（spinal muscular atrophy，SMA）是一种以脊髓运动神经元变性和肌肉萎缩为特征的常染色体隐性遗传神经肌肉疾病。运动神经元存活蛋白（survivalmotorneuronprotein，SMN）是由两个基因SMN 1和SMN 2编码的蛋白质，当SMN 1基因缺失或突变时，可导致选择性脊髓运动神经元变性。先前的报道表明，SMN蛋白缺陷型星形胶质细胞在SMA模型小鼠的脊髓中异常丰富。然而，SMN缺陷型星形胶质细胞异常的机制仍不清楚。本研究的目的是确定与SMN缺陷型星形胶质细胞异常相关的细胞信号传导途径，并提出一种调节信号传导的候选治疗工具。在本研究中，我们发现在小鼠SMA模型中，脊髓中央管周围的星形胶质细胞密度增加，并且我们确定了Notch信号传导的失调，Notch信号传导是SMA发病机制的早期和晚期脊髓中调节星形胶质细胞分化和增殖的已知机制。此外，Notch信号传导的药理学抑制改善了SMA模型小鼠的运动功能缺陷。这些发现表明，Notch信号转导失调可能是SMA病理学的根本原因。
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, namelySMN1andSMN2, but leads to selective spinal motor neuron degeneration whenSMN1gene 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.