FTD risk factor TMEM106B alters endolysosomal function and progranulin pathways

FTD 危险因素 TMEM106B 改变内溶酶体功能和颗粒体蛋白前体途径

• 批准号: 8657519
• 负责人: Johanna I Busch
• 金额: $ 2.87万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-12-01 至 2016-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8657519
• 关键词: Accounting; Affect; Age; Autophagosome; Biochemistry; Cell Fractionation; Cell Line; Cells; Conditioned Culture Media; Data; Dementia; Development; Diagnosis; Disease; Dominant-Negative Mutation; EGF gene; Endosomes; Epidermal Growth Factor Receptor; Equilibrium; Fibrinogen; Frontotemporal Dementia; Frontotemporal Lobar Degenerations; Functional disorder; Genes; Genetic; Genotype; Growth Factor; Haplotypes; Hippocampus (Brain); IGF Type 2 Receptor; Immunoblotting; Immunofluorescence Immunologic; Immunohistochemistry; Incubated; Individual; Integral Membrane Protein; Label; Learning; Lysosomes; Measures; Mediating; Messenger RNA; Microglia; Mus; Mutation; Neurites; Neurodegenerative Disorders; Neurons; Organelles; PGRN gene; Pathogenesis; Pathway interactions; Patients; Phenotype; Physiologic pulse; Plasma; Play; Progranulin; Property; Proteins; Recombinants; Recycling; Risk; Risk Factors; Role; Single Nucleotide Polymorphism; Staining method; Stains; Therapeutic; Time; Transferrin; Work; early onset; effective therapy; extracellular; genetic variant; genome wide association study; human old age (65+); immortalized cell; knock-down; late endosome; neuronal survival; novel; novel therapeutic intervention; overexpression; paracrine; protein TDP-43; public health relevance; research study; therapeutic target; trafficking

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.

项目总结/摘要 额颞叶痴呆（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，并且通常在诊断后的五年内致命。目前还没有有效 治疗学最近发现基因TMEM 106 B中的单核苷酸多态性（SNP）是一种风险， FTLD-TDP是FTD的主要神经病理学子集。TMEM 106 B风险基因型也是 与较高的TMEM 106 B水平、较低的血浆颗粒蛋白前体水平和较早的疾病发作相关， 携带颗粒蛋白前体基因突变的患者。这种对颗粒蛋白前体的影响是显著的，因为约10%的FTLD- TDP是由这种神经营养生长因子的突变引起的。这些疾病相关的突变导致 颗粒蛋白前体的表达或分泌减少，因此颗粒蛋白前体不足似乎 成为疾病的主要驱动力。考虑到TMEM 106 B对颗粒蛋白前体的影响，早期的努力已经做出 了解更多TMEM 106 B，一种特征最少的蛋白质。初步证据显示， TMEM 106 B的表达改变了细胞的内溶酶体平衡， 颗粒蛋白前体，增加其细胞内水平。这项建议的主要前提是， 与FTLD-TDP风险单倍型相关的TMEM 106 B，1）改变和损害内-溶酶体 途径和功能和2）这种内溶酶体扰动损害颗粒蛋白前体运输， 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TMEM 106 B在内溶酶体途径中的功能，并阐明其机制， 增加的TMEM 106 B导致内溶酶体不平衡2）为了确定 TMEM 106 B对颗粒蛋白前体水平的影响，并评估改变的TMEM 106 B水平是否影响颗粒蛋白前体的 神经营养作用为了实现这些目标，免疫组织化学、生物化学、亚细胞分级， 并且存活实验将在永生化细胞系以及原代小鼠神经元中进行。 阐明TMEM 106 B的正常功能及其在疾病中的功能障碍可以产生重要的 治疗目标将集中在恢复颗粒蛋白前体的神经营养作用。