Corticospinal Motor Neurons Are Susceptible to Increased ER Stress and Display Profound Degeneration in the Absence of UCHL1 Function.
Corticospinal Motor Neurons Are Susceptible to Increased ER Stress and Display Profound Degeneration in the Absence of UCHL1 Function.
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DOI：
10.1093/cercor/bhu318
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发表时间：
2015-11
期刊：
影响因子：
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通讯作者：
Özdinler PH
中科院分区：
文献类型：
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作者：
Jara JH;Genç B;Cox GA;Bohn MC;Roos RP;Macklis JD;Ulupınar E;Özdinler PH
皮质脊髓运动神经元（CSMN）接收、整合并传递大脑皮层对脊髓目标的输入，以启动和调节随意运动。CSMN变性是许多运动神经元疾病和神经退行性疾病的中心。此前，有5例泛素羧基末端水解酶- l1 （UCHL1）基因突变的患者被报道为神经变性和运动神经元功能障碍，并累及上运动神经元。为了研究UCHL1对CSMN健康和稳定性的作用，我们采用了体内和体外两种方法，并利用了缺乏所有UCHL1功能的uch1nm3419 （UCHL1−/−）小鼠。我们报道了UCHL1在维持CSMN活力和细胞完整性方面的独特作用。在没有UCHL1的情况下，CSMN表现为早期、选择性、进行性和深度的细胞损失。CSMN变性，即使在症状前阶段也很明显，表现为根尖树突解体和脊柱丢失，是通过内质网应激增加介导的。这些发现为CSMN易感性的基础带来了新的认识，并建议UCHL1 - / -小鼠作为研究CSMN病理的工具。
Corticospinal motor neurons (CSMN) receive, integrate, and relay cerebral cortex's input toward spinal targets to initiate and modulate voluntary movement. CSMN degeneration is central for numerous motor neuron disorders and neurodegenerative diseases. Previously, 5 patients with mutations in the ubiquitin carboxy-terminal hydrolase-L1 (UCHL1) gene were reported to have neurodegeneration and motor neuron dysfunction with upper motor neuron involvement. To investigate the role of UCHL1 on CSMN health and stability, we used both in vivo and in vitro approaches, and took advantage of the Uchl1nm3419 (UCHL1−/−) mice, which lack all UCHL1 function. We report a unique role of UCHL1 in maintaining CSMN viability and cellular integrity. CSMN show early, selective, progressive, and profound cell loss in the absence of UCHL1. CSMN degeneration, evident even at pre-symptomatic stages by disintegration of the apical dendrite and spine loss, is mediated via increased ER stress. These findings bring a novel understanding to the basis of CSMN vulnerability, and suggest UCHL1−/− mice as a tool to study CSMN pathology.