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）：溶酶体功能障碍已与许多神经退行性疾病有关，包括成年的阿尔茨海默氏症和帕金森氏病。几条证据表明，溶酶体功能障碍是额颞叶变性的关键疾病机制，其泛素阳性夹杂物（FTLD-U）是阿尔茨海默氏病后最普遍的早期发作痴呆。尿素（PGRN）基因的单倍不足已被鉴定为FTLD-U的主要原因，并且纯合PGRN突变的患者会发展出神经元CEROID脂肪肌动症（NCL），一种溶酶体储存障碍。这表明PGRN在调节溶酶体功能中起着核心作用。在FTLD-U-VCP/P97和CHMP2B-solso中突变的其他基因调节内溶液体贩运。此外，TMEM106B是FTLD-U具有PGRN突变的新遗传危险因素，是一种溶酶体膜蛋白，TMEM106B水平升高会导致溶酶体功能障碍和FTLD-U的风险增加。我们的研究将检查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结合伙伴还将测试其在溶酶体中的功能。在AIM2中，我们将探测调节TMEM106B水平和功能的细胞机制。特别是，我们的研究将研究受调节的膜内蛋白水解（RIP）和泛素化的作用。在AIM3中，我们将使用病毒介导的基因输送到模拟FTLD-U病例的野生型和PGRN缺乏条件的TMEM106B水平升高的体外和体内表型进行比较。我们还将探讨TMEM106B对PGRN代谢的影响。这些提出的研究将揭示在调节TMEM106B的溶酶体和细胞途径中的TMEM106B功能。我们希望这项研究能够说明FTLD-U中TMEM106B和PGRN之间的相互作用，并为FTLD-U疗法提供基础。重要的是，这项工作还将对溶酶体功能调节的调节产生更广泛的见解，这些溶酶体功能可能应用于其他各种神经退行性疾病。