Function of TMEM106B in neurodegeneration

TMEM106B 在神经退行性变中的功能

• 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
• 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' 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

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 最初被确定为伴有颗粒蛋白 (GRN) 突变的额颞叶痴呆 (FTD) 的危险因素，最近与许多其他神经退行性疾病相关，包括阿尔茨海默病 (AD)、帕金森病和边缘系统年龄相关性 TDP-43 脑病 (LATE)。 TMEM106B 也被认为是大脑衰老的主要决定因素之一。更有趣的是，最近发现 TMEM106B 管腔结构域中的 D252N 突变会导致髓鞘性脑白质营养不良 (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 缺陷导致核周区域溶酶体聚集以及轴突初始段 (AIS) 中溶酶体运输受阻。 TMEM106B 缺陷小鼠表现出自噬缺陷和 FTD 相关病理，例如衰老过程中磷酸化 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形成、自噬、大脑衰老和 TDP-43 病理。我们计划使用细胞生物学和生化方法确定 TMEM106B 调节溶酶体定位、溶酶体沿轴突运输和自噬流的机制 (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。由于核周区域溶酶体聚集增加和溶酶体胞吐作用减少，TMEM106B 的消融会导致髓磷脂膜蛋白 PLP 的运输缺陷。我们计划进一步表征 TMEM106B 缺陷小鼠的髓鞘形成缺陷，尤其是 AIS 区域附近，并确定 D252N 突变对 TMEM106B 功能和髓鞘形成的影响 (Aim2)。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、神经胶质活化、神经变性和 TDP-43 聚集体的积累。我们计划使用小鼠模型和人类患者样本进一步剖析 TMEM106B 如何与 GRN 进行基因相互作用，以调节 TDP-43 病理学和 FTD 疾病进展 (Aim3)。总之，拟议的研究将揭示 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 相关的许多脑部疾病（包括 HLD、LATE、AD 和 FTD）的分子和细胞机制。我们的工作还将对 AD、FTD 和 LATE 中 TDP-43 聚集的调节机制以及髓鞘形成缺陷如何导致 AD、FTD 和其他脑部疾病的神经退行性表型产生新的见解。