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

由于神经元不会分裂，每次分裂都会稀释细胞质，因此它们需要有更好的控制 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 疾病表现为蛋白质的堆积、沉积和聚集。即使形成的蛋白质 聚集物在不同疾病之间表现出差异，可能有一些共同的潜在原因。其中一个 神经元用来控制蛋白质周转的机制是泛素蛋白小体系统(UPS)，它依赖于 免费泛素的可用性。UPS功能失效导致蛋白质清除缺陷、内质网应激增加 自噬和细胞退化。泛素羧基末端水解酶L1(UCHL1)是一种独特的配对基因 连接酶和水解酶的活性，在确认其独特的维持作用后得到了极大的关注 神经元内的游离泛素水平。UCHL1基因突变与运动障碍有关 帕金森氏症患者，以及最近发生的涉及上运动神经的早期神经变性 大脑皮层中的神经元。越来越多的证据还表明，脑内UCHL1蛋白水平降低 患有神经退行性疾病的患者。在这个提案中，我们将重点研究上运动神经元，并研究 UCHL1在这一神经元群体的健康和稳定中的作用。我们认为上运动神经元是 大脑皮层的代言人为运动神经元回路，其退行性变导致各种 遗传性痉挛截瘫、原发性侧索硬化症等神经退行性疾病及其退行性疾病 肌萎缩侧索硬化症的脊髓运动神经元。这项提议将带来一种机械论的见解 并将揭示UCHL1的作用，以及更广泛地说，UCHL1的功能 不适当的UPS对上运动神经元的健康和稳定性的影响。

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.