Role of TFEB in Tauopathy

TFEB 在 Tau 蛋白病中的作用

基本信息

批准号：
9063627
负责人：
Hui Zheng
金额：
$ 41.12万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9063627
关键词：
Address Adult Adverse effects Alzheimer&apos s Disease Animals Astrocytes Autophagocytosis Axon Behavioral Binding Brain Cells Dendrites Dependovirus Development Disease Dissociation Endocytosis Exhibits Exocytosis Frontotemporal Dementia Gene Expression Gene Targeting Goals Health Human In Vitro Injection of therapeutic agent Intercellular Fluid Knock-out Lysosomes Measures Mediating Microdialysis Microtubules Mus Nerve Degeneration Neurodegenerative Disorders Neurofibrillary Tangles Neuroglia Neurons Pathogenesis Pathology Pathway interactions Patients Physiological Play Prevention Proteins Regulation Role Staging Tauopathies Testing Therapeutic Transcriptional Activation Transgenic Mice Transgenic Organisms Wild Type Mouse abnormally phosphorylated tau cellular targeting effective therapy extracellular gain of function hyperphosphorylated tau in vivo innovation insight loss of function mouse model mutant neuropathology novel overexpression prevent prion-like tau Proteins tau aggregation therapy development transcription factor transmission process uptake

项目摘要

DESCRIPTION (provided by applicant): Tauopathies consist of a group of diseases, including frontotemporal dementias and the most common form Alzheimer's disease, and are characterized by the accumulation of intracellular neurofibrillary tangles (NFTs) composed of aggregates of hyperphosphorylated Tau protein and extensive neurodegeneration. Tau is normally localized to the neuronal axons where it binds and stabilizes the microtubules. Aberrant Tau phosphorylation leads to its dissociation from the microtubules followed by aggregation and redistribution to cell bodies and dendrites. In addition, Tau has been shown to be secreted, and this mechanism has been implicated in the prion-like transfer of Tau pathology. Accumulating evidence has implicated impaired autophagy-lysosome pathway in neurodegenerative diseases including Alzheimer's disease. Recently, the Transcription Factor EB (TFEB) was discovered as a master regulator of cellular clearance through coordinated expression of autophagy and lysosomal target genes. We found that TFEB is highly efficacious in ameliorating phospho-Tau/NFT pathology, neurodegeneration, and behavioral deficits in rTg4510 Tau transgenic mice while exhibiting no adverse effect on wild-type mice; TFEB is effective when introduced both before and after the onset of neuropathology. Besides the autophagy-lysosome pathway, substantial evidence also supports a non-cell-autonomous role of TFEB in cellular clearance through neuronal exocytosis and astroglial-mediated endocytosis. Therefore, we hypothesize in this proposal that TFEB promotes lysosomal exocytosis and subsequent astroglial uptake of Tau, and that TFEB-mediated glial uptake of extracellular Tau prevents cell-to-cell transfer of the NFT-like pathology. We are equipped with sophisticated mouse models and innovative approaches that allow us to address these questions in vitro and in vivo at the subcellular, cellular, and network levels. At the completion of the proposal, we wil have gained mechanistic and functional insights into the poorly defined role of astrocytes in Tau clearance and the interplay between neurons and astrocytes in mediating Tau pathogenesis.

描述（由适用提供）：tauopathies由一组疾病组成，包括额叶痴呆症和最常见的阿尔茨海默氏病，其特征是由细胞内神经纤维缠结（NFTS）积累，由高磷酸化的TAU蛋白质蛋白和广泛的神经变性组成。 tau通常位于神经轴突，在该轴突结合并稳定微管。异常的tau磷酸化导致其与微管的解离，然后聚集和重新分布到细胞体和树突。此外，TAU已被证明是分泌的，并且该机制已在Tau病理学的prion样转移中实现。累积的证据已被实施，包括在包括阿尔茨海默氏病在内的神经退行性疾病中的自噬 - 溶酶体途径受损。最近，转录因子EB（TFEB）是作为大师的，我们发现TFEB在改善磷酸化/NFT病理学，神经变性和行为方面的效率很高，而行为却定义了RTG4510 TAU转基因小鼠，而对野生型小鼠的转移无效。在神经病理学开始之前和之后引入TFEB都是有效的。除了自噬 - 散肌体途径外，大量证据还支持TFEB通过神经元胞吐作用和星形胶质细胞介导的内吞作用在细胞清除中的非细胞自主作用。因此，我们在这一提议中假设TFEB促进了Tau的溶酶体胞吐作用和随后的星形胶质细胞摄取，并且TFEB介导的细胞外TAU的神经胶质摄取可防止NFT样病理学的细胞对细胞向细胞转移。我们配备了复杂的小鼠模型和创新方法，使我们能够在亚细胞，细胞和网络水平上在体外和体内解决这些问题。提案完成时，我们已经获得了机械和功能性的见解，以了解星形胶质细胞在TAU清除率中的作用不当，以及神经元与星形胶质细胞之间的相互作用在中介Tau发病机理中的相互作用。