FTD risk factor TMEM106B alters endolysosomal function and progranulin pathways

项目摘要/摘要 额颞性痴呆(FTD)是一种神经退行性疾病，占痴呆病例的10%-20% 年龄在65岁以下，通常在确诊后五年内死亡。目前还没有有效的 治疗学。最近发现TMEM106B基因的单核苷酸多态(SNPs)是一种风险因素 FTLD-TDP是FTD的一个主要神经病理亚群。TMEM106B风险基因也是 与较高的TMEM106B水平、较低的血浆原颗粒水平和较早的疾病发病有关 携带前颗粒蛋白基因突变的患者。这对原颗粒的影响是显著的，因为~10%的FTLD- TDP是由这种神经营养生长因子的突变引起的。这些与疾病相关的突变导致 原颗粒的表达减少或分泌减少，因此原颗粒不足似乎 成为疾病的主要驱动力。鉴于TMEM106B对原颗粒蛋白的影响，早期的努力是 了解更多TMEM106B，一种最小特征的蛋白质。初步证据表明， TMEM106B的表达改变了细胞内溶酶体的平衡以及细胞的分布 原颗粒，增加其细胞内水平。这项提议的主要前提是增加水平 与FTLD-TDP风险单倍型相关的TMEM106B，1)改变和损害内溶酶体 途径和功能以及2)这种内切酶体扰动损害原颗粒运输， 导致其神经营养作用的丧失。根据这一前提，我们追求以下几个目标：1) 确定TMEM106B在内切酶途径中的功能并阐明其作用机制 增加的TMEM106B导致内溶酶体失衡2)以确定其机制 TMEM106B对原颗粒蛋白水平的影响以及TMEM106B水平变化是否影响原颗粒蛋白 神经营养作用。在追求这些目标的过程中，免疫组织化学、生物化学、亚细胞分离、 存活实验将在永生化细胞系和原代小鼠神经元中进行。 阐明TMEM106B的正常功能及其在疾病中的功能障碍将产生重要的 专注于恢复原颗粒的神经营养作用的治疗目标。

Project Summary / Abstract Frontotemporal dementia (FTD) is a neurodegenerative disease that accounts for 10-20% of dementia cases under the age of 65 and is typically fatal within the five years of diagnosis. There are currently no effective therapeutics. Single nucleotide polymorphisms (SNPs) in the gene TMEM106B were recently found to be a risk factor in FTLD-TDP, a major neuropathological subset of FTD. The TMEM106B risk genotype is also associated with higher TMEM106B levels, lower plasma progranulin levels, and earlier onset of disease in patients carrying mutations in the progranulin gene. This effect on progranulin is notable, as ~10% of FTLD- TDP is caused by mutations in this neurotrophic growth factor. These disease-associated mutations result in either decreased expression or decreased secretion of progranulin, and thus insufficient progranulin seems to be a major driver of disease. Given the effects of TMEM106B on progranulin, early efforts have been made to learn more TMEM106B, a minimally characterized protein. Preliminary evidence has shown that increased expression of TMEM106B alters the endolysosomal equilibrium of cells as well as the distribution of progranulin, increasing its intracellular levels. The major premise of this proposal is that increased levels of TMEM106B, as associated with the FTLD-TDP risk haplotype, 1) alter and impair endo-lysosomal pathways and functions and 2) that this endolysosomal perturbation impairs progranulin trafficking, resulting in the loss of its neurotrophic effects. In line with this premise, several aims are pursued: 1) To determine the function of TMEM106B in the endolysosomal pathway and elucidate the mechanism by which increased TMEM106B results in endolysosomal disequilibrium 2) To determine the mechanism of TMEM106B's effect on progranulin levels and assess if altered TMEM106B levels affect progranulin's neurotrophic effects. In pursuit of these aims, immunohistochemistry, biochemistry, subcellular fractionation, and survival experiments will be conducted in immortalized cell lines as well as in primary mouse neurons. Elucidation of the normal function of TMEM106B and its dysfunction in disease could yield important therapeutic targets that would focus on restoring progranulin's neurotrophic effects.