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

UCHL1对上运动神经元健康和稳定性的作用

基本信息

批准号：
8877655
负责人：
Pembe Hande Ozdinler
金额：
$ 33.8万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-15 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8877655
关键词：
ARHGEF5 gene Affect Amyotrophic Lateral Sclerosis Anatomy Apical Attention Autophagocytosis Axon Biology Birth Brain Cells Cerebral cortex Cytoplasm Defect Dendrites Dendritic Spines Deposition Deubiquitinating Enzyme Development Diagnosis Disease Electroporation Failure Future Gene Delivery Genes Goals Health Hereditary Spastic Paraplegia Homeostasis Hydrolase In Vitro Knockout Mice Label Length Life Ligase Link Literature Mediating Molecular Motor Cortex Motor Neuron Disease Motor Neurons Movement Movement Disorders Mus Mutation Nerve Degeneration Neurodegenerative Disorders Neurons Parkinson Disease Pathway interactions Patients Persons Population Primary Lateral Sclerosis Proteins Reporter Role Spinal Staging Stress System Translating Ubiquitin Variant cellular pathology effective therapy hippocampal pyramidal neuron human data in utero in vivo insight molecular marker motor neuron degeneration multicatalytic endopeptidase complex neuronal cell body novel promoter protein degradation pup small hairpin RNA tool treatment strategy ubiquitin C-terminal hydrolase

项目摘要

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.

描述（由申请人提供）：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其蛋白质含量和蛋白质周转机制。几乎所有神经退行性疾病都表现出蛋白质积累、沉积和聚集，这并不奇怪。尽管形成聚集体的蛋白质在疾病之间表现出差异，但可能存在一些共同的根本原因。神经元用来控制蛋白质周转的机制之一是泛素蛋白酶体系统 (UPS)，它取决于游离泛素的可用性。 UPS 功能失败会导致蛋白质清除缺陷、内质网应激、自噬增加和细胞变性。泛素羧基末端水解酶 L1 (UCHL1) 是一种独特的 DUB，具有连接酶和水解酶活性，在确定其在维持神经元内游离泛素水平方面的独特作用后，受到广泛关注。 UCHL1基因突变与帕金森病患者的运动障碍有关，最近还与涉及大脑皮层上运动神经元的早期神经变性有关。越来越多的证据还表明，神经退行性疾病患者大脑中 UCHL1 蛋白的水平降低。在本提案中，我们将重点关注上运动神经元，并研究 UCHL1 对于该神经元群健康和稳定性的作用。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”，它们的退化会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，以及肌萎缩侧索硬化症中的脊髓运动神经元一起退化。该提案将为上运动神经元变性带来机制上的洞察，并将揭示 UCHL1 的作用，以及更广泛地揭示不当 UPS 对上运动神经元健康和稳定性的功能。