Absence of alsin function leads to corticospinal motor neuron vulnerability via novel disease mechanisms.
Absence of alsin function leads to corticospinal motor neuron vulnerability via novel disease mechanisms.
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DOI：
10.1093/hmg/ddv631
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发表时间：
2016-03-15
影响因子：
3.5
通讯作者：
Özdinler PH
中科院分区：
文献类型：
--
作者：
Gautam M;Jara JH;Sekerkova G;Yasvoina MV;Martina M;Özdinler PH
ALS 2基因突变导致早发性肌萎缩侧索硬化症、突发性上行性遗传性痉挛性截瘫和青少年原发性侧索硬化症，表明上运动神经元受累明显。然而，alsin功能对皮质脊髓运动神经元（CSMN）健康和稳定的重要性仍然未知。迄今为止，已经产生了四种单独的Alsin敲除（AlsinKO）小鼠模型，尽管希望模仿人类病理学，但没有一种显示出严重的运动功能缺陷。然而，这并不排除CSMN内神经元缺陷的可能性，这在这些小鼠中不容易检测到。由于CSMN的数量有限以及大脑皮层的复杂性和异质性，对CSMN的详细细胞分析受到阻碍。为了在体内可视化CSMN并研究在缺乏alsin功能的情况下神经元异常的精确方面，我们通过将AlsinKO和UCHL 1-eGFP小鼠（CSMN报告细胞系）杂交来产生AlsinKO-UeGFP小鼠。我们发现，CSMN显示空泡化的顶端树突，自噬增加，索马大小收缩和轴突病理，甚至在脑桥区域。免疫细胞化学结合电镜观察表明，苜蓿素对维持细胞结构和细胞器的完整性具有重要作用。在它的情况下，CSMN显示在线粒体和高尔基体的选择性缺陷。UCHL 1-eGFP小鼠有助于了解导致疾病中CSMN脆弱性的潜在细胞因素，我们的研究结果揭示了Alsin功能对CSMN健康和稳定的独特重要性。
Mutations in the ALS2 gene result in early-onset amyotrophic lateral sclerosis, infantile-onset ascending hereditary spastic paraplegia and juvenile primary lateral sclerosis, suggesting prominent upper motor neuron involvement. However, the importance of alsin function for corticospinal motor neuron (CSMN) health and stability remains unknown. To date, four separate alsin knockout (AlsinKO) mouse models have been generated, and despite hopes of mimicking human pathology, none displayed profound motor function defects. This, however, does not rule out the possibility of neuronal defects within CSMN, which is not easy to detect in these mice. Detailed cellular analysis of CSMN has been hampered due to their limited numbers and the complex and heterogeneous structure of the cerebral cortex. In an effort to visualize CSMN in vivo and to investigate precise aspects of neuronal abnormalities in the absence of alsin function, we generated AlsinKO-UeGFP mice, by crossing AlsinKO and UCHL1-eGFP mice, a CSMN reporter line. We find that CSMN display vacuolated apical dendrites with increased autophagy, shrinkage of soma size and axonal pathology even in the pons region. Immunocytochemistry coupled with electron microscopy reveal that alsin is important for maintaining cellular cytoarchitecture and integrity of cellular organelles. In its absence, CSMN displays selective defects both in mitochondria and Golgi apparatus. UCHL1-eGFP mice help understand the underlying cellular factors that lead to CSMN vulnerability in diseases, and our findings reveal unique importance of alsin function for CSMN health and stability.