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Function of TMEM106B in neurodegeneration

TMEM106B 在神经退行性变中的功能

基本信息

批准号：
10380810
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/10380810
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 Light Lysosomes Membrane Proteins Modeling Molecular Movement Mus Mutation Myelin Myelin Sheath Nerve Degeneration Neurodegenerative Disorders Nuclear Oligodendroglia Organism Parkinson Disease Pathology Patients Phenotype Physiological Positioning Attribute Proteins Proteomics Regulation Risk Risk Factors Role Sampling Structure TDP-43 aggregation Testing Vacuole 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.

溶酶体跨膜蛋白TMEM106B最初被确定为颗粒素(GRN)突变的额颞叶痴呆(FTD)的危险因素，最近被发现与许多其他神经退行性疾病有关，包括阿尔茨海默氏症(AD)、帕金森氏症和边缘占优势的年龄相关TDP-43脑病(LATE)。TMEM106B也被认为是脑老化的主要决定因素之一。更有趣的是，最近发现TMEM106B管腔区域的D252N突变会导致低髓素性脑白质营养不良(HLD)。然而，TMEM106B的细胞和生理功能仍有待确定。在我们的初步研究中，我们发现TMEM106B缺乏导致溶酶体聚集在核周区域和轴突起始段(AIS)的溶酶体运输受阻。TMEM106B基因缺陷的小鼠表现出自噬缺陷和FTD相关的病理，例如在衰老过程中磷酸化的TDP-43积累。我们推测TMEM106B通过调节溶酶体运输和运动来调节髓鞘形成、自噬、脑老化和TDP-43病理。我们计划利用细胞生物学和生化方法(Aim1)确定TMEM106B调节溶酶体定位、溶酶体沿轴突运输和自噬流动的机制(Aim1)。我们的研究还表明，TMEM106B在少突胶质细胞中高表达，TMEM106B缺乏会导致小鼠髓鞘形成缺陷。TMEM106B的消融导致髓鞘膜蛋白PLP的运输缺陷，这是由于溶酶体聚集在核周区域并降低了溶酶体的胞吐作用。我们计划进一步鉴定TMEM106B缺陷小鼠的髓鞘缺陷，特别是在AIS区域附近，并确定D252N突变对TMEM106B功能和髓鞘形成(AIM2)的影响。最后，我们发现同时缺乏TMEM106B和GRN的小鼠存在严重的溶酶体异常，胶质细胞激活，神经变性和TDP-43聚集体积聚。我们计划利用小鼠模型和人类患者样本(Aim3)进一步剖析TMEM106B如何与GRN在遗传上相互作用，以调控TDP-43的病理和FTD疾病的进展(Aim3)。综上所述，这些研究将有助于阐明TMEM106B的细胞和生理功能、GRN和TMEM106B之间的遗传相互作用以及与TMEM106B相关的许多脑疾病的分子和细胞机制，包括HLD、LATE、AD和FTD。我们的工作还将对AD、FTD和LATE中调节TDP-43聚集的机制以及髓鞘缺陷如何导致AD、FTD和其他大脑疾病的神经退行性变表型有新的见解。