Function of TMEM106B in neurodegeneration

TMEM106B 在神经退行性变中的功能

• 批准号: 8750376
• 负责人: Fenghua Hu
• 金额: $ 35.18万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8750376
• 关键词: Accounting; Adenoviruses; Adult; Affect; Age of Onset; Alzheimer' s Disease; Binding; Biological; Biological Assay; Cell physiology; Cells; Characteristics; Clustered Regularly Interspaced Short Palindromic Repeats; Data; Dementia; Development; Disease; Disease Association; Disease Progression; Exhibits; Foundations; Frontotemporal Lobar Degenerations; Functional disorder; Gene Delivery; Genes; Genetic Polymorphism; Human; Impaired cognition; In Vitro; Inherited; Life; Light; Link; Lysosomes; Mediating; Membrane Proteins; Metabolism; Molecular; Morphology; Mus; Mutate; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neuronal Ceroid-Lipofuscinosis; Neurons; PGRN gene; Parkinson Disease; Pathway interactions; Patients; Phenotype; Physiological; Play; Process; Progranulin; Proteins; Proteolysis; Proteomics; Regulation; Research; Risk; Risk Factors; Role; Single Nucleotide Polymorphism; System; Testing; Therapeutic; Therapeutic Intervention; Transmission Electron Microscopy; Ubiquitin; Ubiquitination; Virus; Work; base; cellular imaging; drug development; early onset; frontal lobe; genetic risk factor; in vivo; insight; late endosome; neurodegenerative phenotype; novel; overexpression; protein TDP-43; protein aggregate; public health relevance; trafficking

DESCRIPTION (provided by applicant): Lysosomal dysfunction has been implicated in many neurodegenerative diseases, including adult onset Alzheimer's and Parkinson's diseases. Several lines of evidence point to lysosomal dysfunction as a critical disease mechanism in frontotemporal lobar degeneration with ubiquitin positive inclusions (FTLD-U)-the most prevalent early onset dementia after Alzheimer's disease. The haplo- insufficiency of the Progranulin (PGRN) gene has been identified as a major cause of FTLD-U, and patients with homozygous PGRN mutations develop neuronal ceroid lipofuscinosis (NCL), a lysosomal storage disorder. This suggests that PGRN plays a central role in regulating lysosomal function. Other genes mutated in FTLD-U-VCP/p97 and CHMP2B-also regulate endolysosomal trafficking. Further, TMEM106B, a newly identified genetic risk factor for FTLD-U with PGRN mutations, is a lysosomal membrane protein, and increased TMEM106B levels result in lysosomal dysfunction and increased risk for FTLD-U. Our research will examine the physiological functions of TMEM106B in lysosomes and their role in neurodegeneration. In Aim1, we will use molecular and cell biological approaches to determine how TMEM106B regulates lysosomal activities and lysosomal dynamics. Potential TMEM106B binding partners will also be tested for their function in lysosomes. In Aim2, we will probe cellular mechanisms that regulate TMEM106B levels and function. In particular, our research will examine the role of regulated intramembrane proteolysis (RIP) and ubiquitination. In Aim3, we will compare the in vitro and in vivo phenotypes of elevated TMEM106B levels in wild type and PGRN deficient conditions using virus mediated gene delivery to mimic FTLD-U cases. We will also explore the effect of TMEM106B on PGRN metabolism. These proposed studies will shed light on TMEM106B function in lysosomes and cellular pathways that regulate TMEM106B. We hope this research will illustrate the interaction between TMEM106B and PGRN in FTLD-U and provide the foundation for FTLD-U therapeutics. Importantly, this work will also generate broader insights into the regulation of lysosomal function that may be applied in a variety of other neurodegenerative diseases.

描述（由申请人提供）：溶酶体功能障碍与许多神经退行性疾病有关，包括成人发病的阿尔茨海默病和帕金森病。一些证据表明溶酶体功能障碍是泛素阳性包涵体（FTLD-U）额颞叶变性（阿尔茨海默病后最常见的早发性痴呆）的关键疾病机制。前颗粒蛋白（PGRN）基因的单倍体不足已被确定为FTLD-U的主要原因，纯合子PGRN突变的患者会发展为神经性ceroid脂褐质病（NCL），一种溶酶体储存障碍。这表明PGRN在调节溶酶体功能中起核心作用。在FTLD-U-VCP/p97和chmp2b中突变的其他基因也调节内溶酶体的运输。此外，TMEM106B是一种溶酶体膜蛋白，是新发现的FTLD-U伴PGRN突变的遗传危险因素，TMEM106B水平升高导致溶酶体功能障碍，增加FTLD-U的风险。我们的研究将探讨TMEM106B在溶酶体中的生理功能及其在神经变性中的作用。在Aim1中，我们将使用分子和细胞生物学方法来确定TMEM106B如何调节溶酶体活性和溶酶体动力学。潜在的TMEM106B结合伙伴也将测试其在溶酶体中的功能。在ai2中，我们将探讨调节TMEM106B水平和功能的细胞机制。特别是，我们的研究将检查调节膜内蛋白水解（RIP）和泛素化的作用。在aims中，我们将使用病毒介导的基因传递模拟FTLD-U病例，比较野生型和PGRN缺陷条件下TMEM106B水平升高的体外和体内表型。我们还将探讨TMEM106B对PGRN代谢的影响。这些拟议的研究将阐明TMEM106B在溶酶体中的功能和调节TMEM106B的细胞途径。我们希望本研究能够阐明TMEM106B和PGRN在FTLD-U中的相互作用，为FTLD-U的治疗提供基础。重要的是，这项工作还将对溶酶体功能的调节产生更广泛的见解，这可能应用于各种其他神经退行性疾病。