Function of TMEM106B in neurodegeneration

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。几条证据表明，溶酶体功能障碍是额颞叶变性伴泛素阳性包涵体（FTLD-U）-阿尔茨海默病后最常见的早发性痴呆-的关键疾病机制。颗粒蛋白前体（PGRN）基因的单倍型不足已被鉴定为FTLD-U的主要原因，并且具有纯合PGRN突变的患者发展神经元蜡样质脂褐质沉积症（NCL），一种溶酶体贮积症。这表明PGRN在调节溶酶体功能中起核心作用。在FTLD-U-VCP/p97和CHMP 2B中突变的其他基因也调节内溶酶体运输。此外，TMEM 106 B是一种新鉴定的具有PGRN突变的FTLD-U的遗传风险因子，是一种溶酶体膜蛋白，TMEM 106 B水平升高导致溶酶体功能障碍和FTLD-U风险升高。我们的研究将检查TMEM 106 B在溶酶体中的生理功能及其在神经变性中的作用。在Aim 1中，我们将使用分子和细胞生物学方法来确定TMEM 106 B如何调节溶酶体活性和溶酶体动力学。还将测试潜在的TMEM 106 B结合配偶体在溶酶体中的功能。在Aim 2中，我们将探索调节TMEM 106 B水平和功能的细胞机制。特别是，我们的研究将探讨调节膜内蛋白水解（RIP）和泛素化的作用。在Aim 3中，我们将使用病毒介导的基因递送模拟FTLD-U病例，比较野生型和PGRN缺陷条件下TMEM 106 B水平升高的体外和体内表型。我们还将探索TMEM 106 B对PGRN代谢的影响。这些拟议的研究将阐明TMEM 106 B在溶酶体和调节TMEM 106 B的细胞通路中的功能。我们希望这项研究能够阐明TMEM 106 B和PGRN在FTLD-U中的相互作用，并为FTLD-U治疗提供基础。重要的是，这项工作也将产生更广泛的见解，可以应用于各种其他神经退行性疾病的溶酶体功能的调节。

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.