Function of TMEM106B in Neurodegeneration

TMEM106B 在神经退行性疾病中的功能

基本信息

批准号：
10596658
负责人：
Fenghua Hu
金额：
$ 49.71万
依托单位：
CORNELL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10596658
关键词：
Ablation Affect Aging Alzheimer&apos s Disease Autophagocytosis Autopsy Axon Biochemical Biological Brain Brain Diseases Cell Culture Techniques Cell Line Cell physiology Cells Collaborations Defect Development Disease Disease Progression Distal Exhibits Exocytosis Fibroblasts Frontotemporal Dementia Frontotemporal Lobar Degenerations Genetic Gliosis Human In Vitro Integral Membrane Protein Lysosomes Membrane Proteins Modeling Molecular Movement Mus Mutation Myelin Myelin Sheath Nerve Degeneration Neurodegenerative Disorders Nuclear Oligodendroglia Organism Parkinson Disease Pathology Patients Phenotype Phosphorylation Physiological Positioning Attribute Proteins Proteomics Regulation Risk Risk Factors Role Sampling Structure TDP-43 aggregation Testing Work age related aging brain base druggable target glial activation granulin in vivo insight late endosome leukodystrophy limbic-predominant age-related TDP-43 encephalopathy motor disorder mouse model myelination neurodegenerative phenotype neuron loss novel oligodendrocyte precursor protein TDP-43 protein protein interaction risk variant trafficking

项目摘要

The lysosome transmembrane protein TMEM106B was originally identified as a risk factor for frontotemporal dementia (FTD) with granulin (GRN) mutations and was recently associated with many other neurodegenerative diseases, including Alzheimer’s (AD), Parkinson’s and limbic-predominant age-related TDP-43 encephalopathy (LATE). TMEM106B is also identified as one of the main determinants of brain aging. More interestingly, a D252N mutation in the lumenal domain of TMEM106B was recently found to cause hypomyelinating leukodystrophy (HLD). However, the cellular and physiological functions of TMEM106B remain to be determined. In our preliminary studies, we found that TMEM106B deficiency causes the clustering of lysosomes in the perinuclear region and a block of lysosome transport in the axon initial segment (AIS). TMEM106B deficient mice show autophagy defects and FTD related pathology such as accumulation of phosphorylated TDP-43 during aging. We hypothesize that TMEM106B regulates myelination, autophagy, brain aging and TDP-43 pathology via modulating lysosome trafficking and movement. We plan to determine the mechanisms by which TMEM106B regulates lysosome positioning, lysosome transport along axons and autophagy flow using cell biological and biochemical approaches (Aim1). Our studies have also shown that TMEM106B is highly expressed in oligodendrocytes and TMEM106B deficiency leads to myelination defects in mice. Ablation of TMEM106B leads to trafficking defects of the myelin membrane protein PLP due to increased lysosome clustering in the peri-nuclear region and decreased lysosome exocytosis. We plan to further characterize myelination defects of TMEM106B deficient mice, especially near the AIS region, and determine the effect of the D252N mutation on TMEM106B function and myelination (Aim2). Finally, we found that mice deficient in both TMEM106B and GRN have severe lysosome abnormalities, glial activation, neurodegeneration and accumulation of TDP-43 aggregates. We plan to further dissect how TMEM106B genetically interacts with GRN to regulate TDP-43 pathology and FTD disease progression using mouse models and human patient samples (Aim3). In summary, the proposed studies will shed light on cellular and physiological functions of TMEM106B, the genetic interaction between GRN and TMEM106B and the molecular and cellular mechanisms of many brain disorders with TMEM106B association, including HLD, LATE, AD and, FTD. Our work will also yield novel insights into mechanisms involved in regulating TDP-43 aggregation in AD, FTD and LATE and how myelination defects contribute to neurodegenerative phenotypes in AD, FTD and other brain disorders.

裂解体跨膜蛋白TMEM106B被鉴定为具有颗粒蛋白（GRN）突变的额颞痴呆（FTD）的危险因素，最近与许多其他神经退行性疾病有关，包括阿尔茨海默（AD），帕克森（AD），帕克森（AD），帕克森（Parkinson）和limbic-limbic-age-age-age-aper-aper-preslated-ens-redy-nater-nater-nater-presty-redy-nart-presty-red-nark-red-presty-red-nark-red-143。 TMEM106B也被确定为脑老化的主要决定剂之一。更有趣的是，最近发现在TMEM106B的腔内结构域中发生D252N突变会导致白细胞营养不良（HLD）。但是，TMEM106B的细胞和物理功能仍有待确定。在我们的初步研究中，我们发现TMEM106B缺乏引起核周区域中溶酶体的聚类和轴突初始段（AIS）中的溶酶体转运块。 TMEM106B缺陷小鼠显示自噬缺陷和FTD相关的病理，例如衰老过程中磷酸化的TDP-43的积累。我们假设TMEM106B通过调节溶酶体运输和运动来调节髓鞘，自噬，脑衰老和TDP-43病理。我们计划确定TMEM106B使用细胞生物学和生化方法调节溶酶体定位的机制，沿轴突的溶酶体转运以及自噬流量（AIM1）。我们的研究还表明，TMEM106B在少突胶质细胞中高度表达，而TMEM106B缺乏导致小鼠的骨髓缺陷。 TMEM106B的消融导致髓鞘膜蛋白PLP的交通缺陷，这是由于核糖周围区域中溶酶体聚类的增加而导致的，溶酶体胞吐作用降低。我们计划进一步表征TMEM106B缺陷小鼠的髓鞘缺陷，尤其是在AIS区域附近，并确定D252N突变对TMEM106B功能和髓鞘的影响（AIM2）。最后，我们发现TMEM106B和GRN中具有特异性的小鼠具有严重的溶酶体异常，神经胶质激活，神经变性和TDP-43聚集体的积累。我们计划进一步剖析TMEM106B如何与GRN相互作用，以使用小鼠模型和人类患者样本来调节TDP-43病理和FTD疾病进展（AIM3）。总而言之，拟议的研究将阐明TMEM106B的细胞和物理功能，GRN和TMEM106B之间的遗传相互作用以及许多与TMEM106B关联的许多脑疾病的分子和细胞机制，包括HLD，包括HLD，晚，AD，AD和FTD。我们的工作还将产生对AD，FTD和晚期TDP-43聚集的机制的新见解，以及髓鞘缺陷如何有助于AD，FTD和其他脑疾病中的神经退行性表型。