Role of TFEB in Tauopathy

 描述(由申请人提供)：tauopathy由一组疾病组成，包括额颞部痴呆和最常见的阿尔茨海默病，其特征是细胞内由过度磷酸化的Tau蛋白聚集体组成的神经原纤维缠结(NFT)和广泛的神经变性。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，Tau已被证明是分泌的，这一机制已被认为与Tau病理的Pron样转移有关。越来越多的证据表明，自噬-溶酶体途径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)被发现通过自噬和溶酶体靶基因的协调表达来调节细胞的清除。我们发现，TFEB在改善rTg4510Tau转基因小鼠的磷酸化Tau/NFT病理、神经变性和行为缺陷方面非常有效，而对野生型小鼠没有不良影响；TFEB在神经病理发病前后都是有效的。除了自噬-溶酶体途径外，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进行细胞清除的非细胞自主作用。因此，我们假设TFEB促进溶酶体胞吐和随后星形胶质细胞摄取Tau，并且TFEB介导的胶质细胞摄取细胞外Tau阻止了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，使我们能够在体外和体内在亚细胞、细胞和网络水平上解决这些问题。完成这项提议后，我们将获得对星形胶质细胞在Tau清除中的模糊作用以及神经元和星形胶质细胞之间在介导Tau发病中的相互作用的机制和功能的深入了解。

 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.