Role of TFEB in Tauopathy

 描述（由申请人提供）：Tau病由一组疾病组成，包括额颞叶痴呆和最常见的阿尔茨海默病形式，其特征在于由过度磷酸化的Tau蛋白聚集体和广泛的神经变性组成的细胞内神经元缠结（NFT）的积累。Tau通常定位于神经元轴突，在那里它结合并稳定微管。异常的Tau磷酸化导致其从微管解离，随后聚集并重新分布到细胞体和树突。此外，已经显示Tau是分泌的，并且该机制已经涉及Tau病理的朊病毒样转移。越来越多的证据表明，自噬-溶酶体通路受损与包括阿尔茨海默病在内的神经退行性疾病有关。最近，转录因子EB（TFEB）被发现作为通过自噬和溶酶体靶基因的协调表达的细胞清除的主调节剂。我们发现TFEB在改善rTg 4510 Tau转基因小鼠中的磷酸化Tau/NFT病理、神经变性和行为缺陷方面是高度有效的，同时对野生型小鼠没有表现出不利影响;当在神经病理学发作之前和之后引入TFEB时，TFEB是有效的。除了自噬-溶酶体途径之外，大量证据还支持TFEB通过神经元胞吐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，我们在该提议中假设TFEB促进溶酶体胞吐作用和随后的Tau的星形胶质细胞摄取，并且TFEB介导的细胞外Tau的胶质细胞摄取防止NFT样病理的细胞间转移。我们配备了复杂的小鼠模型和创新的方法，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。在完成该提案时，我们将获得对星形胶质细胞在Tau清除中的定义不清的作用以及神经元和星形胶质细胞在介导Tau发病机制中的相互作用的机制和功能见解。

 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.