The role of UCHL1 on the health and stability of upper motor neurons

由于神经元不分裂，并且每次分裂都会稀释细胞质，因此它们需要更好地控制 它们的蛋白质含量和蛋白质周转机制。毫不奇怪，几乎所有的神经退行性疾病 疾病表现为蛋白质积累、沉积和聚集。即使形成的蛋白质 虽然疾病的总体情况显示不同疾病之间存在差异，但可能存在一些共同的根本原因。之一 神经元用来控制蛋白质周转的机制是泛素蛋白体系统（UPS），它依赖于 游离泛素的可用性。UPS功能失效导致蛋白质清除缺陷、ER应激、增加 自噬和细胞变性。泛素羧基末端水解酶L1（UCHL1）是一种独特的DUB， 连接酶和水解酶活性，并且在鉴定了其在维持 神经元内的游离泛素水平。UCHL1基因的突变与运动障碍有关， 帕金森病患者，以及最近在涉及上运动神经的早期神经退行性变中， 大脑皮层的神经元证据还显示，在大脑中UCHL1蛋白水平降低， 神经退行性疾病患者。在这个建议中，我们将重点放在上运动神经元，并调查 UCHL1对神经元群体的健康和稳定性的作用。我们认为上运动神经元是 “发言人”的大脑皮层的运动神经元电路，和他们的退化导致各种 神经退行性疾病，如遗传性痉挛性截瘫，原发性侧索硬化症， 与肌萎缩侧索硬化症中的脊髓运动神经元一起。这个建议将带来一个机械的洞察力 上运动神经元变性，并将揭示UCHL1的作用，更广泛地说， 不适当的UPS对上运动神经元的健康和稳定性。

Since neurons do not divide, and dilute the cytoplasm with every division, they need to have better controls over their protein content and protein turnover mechanisms. It is not surprising that almost all neurodegenerative diseases display protein accumulations, deposits, and aggregates. Even though the proteins that form aggregates show variation among diseases, there may be some common underlying causes. One of the mechanisms neurons use to control protein turnover is the ubiquitin proteosome system (UPS), which depends on the availability of free ubiquitin. Failure in UPS function results in protein clearance defects, ER-stress, increased autophagy and cellular degeneration. Ubiquitin carboxy-terminal hydrolase L1 (UCHL1) is a unique DUB with both ligase and hydrolase activities and it is gaining much attention after identification of its unique role in maintaining the free ubiquitin levels inside the neurons. Mutations in the UCHL1 gene is linked both to movement disorders in patients with Parkinson's disease, and more recently in early neurodegeneration which involves the upper motor neurons in the cerebral cortex. Building evidence also show reduced levels of UCHL1 protein in the brains of patients with neurodegenerative diseases. In this proposal, we will focus on upper motor neurons, and investigate the role of UCHL1 on the health and stability of this neuron population. We consider upper motor neurons as the "spokesperson"of the cerebral cortex for the motor neuron circuitry, and their degeneration leads to various neurodegenerative diseases such as hereditary spastic paraplegia, primary lateral sclerosis and they degenerate together with spinal motor neurons in amyotrophic lateral sclerosis. This proposal will bring a mechanistic insight into upper motor neuron degeneration and will reveal the role of UCHL1, and more broadly the function of improper UPS on the health and stability of upper motor neurons.