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

描述(申请人提供)：由于神经元不会分裂，每次分裂都会稀释细胞质，因此它们需要更好地控制蛋白质含量和蛋白质周转机制。不足为奇的是，几乎所有的神经退行性疾病都会表现出蛋白质的堆积、沉积和聚集。尽管形成聚集体的蛋白质在不同疾病中表现出不同，但可能存在一些共同的潜在原因。神经元用来控制蛋白质周转的机制之一是泛素蛋白小体系统(UPS)，它依赖于游离泛素的可用性。UPS功能的失效会导致蛋白质清除缺陷、内质网应激、自噬增加和细胞退化。泛素羧基末端水解酶L1(UCHL1)是一种兼具连接酶和水解酶活性的基因，其在维持神经元内游离泛素水平方面的独特作用引起了人们的广泛关注。UCHL1基因的突变既与帕金森氏症患者的运动障碍有关，也与最近涉及大脑皮层上运动神经元的早期神经退行性变有关。越来越多的证据还表明，神经退行性疾病患者大脑中UCHL1蛋白水平降低。在这项提案中，我们将重点关注上运动神经元，并研究UCHL1对这一神经元群体的健康和稳定的作用。我们认为，上运动神经元是大脑皮层运动神经元回路的代言人，它们的退变导致遗传性痉挛截瘫、原发性侧索硬化症等多种神经退行性疾病，在肌萎缩侧索硬化症中它们与脊髓运动神经元一起退变。这一提议将为上运动神经元的退化带来一个机械性的洞察，并将揭示UCHL1的作用，以及更广泛地说，不适当的UPS对上运动神经元的健康和稳定的作用。

DESCRIPTION (provided by applicant): 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.