Kondalarao Bankapalli, Ruth E Thomas, Evelyn S Vincow, Gillian Milstein, Laura V Fisher, Leo J Pallanck
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引用次数: 0
Abstract
Brain protein aggregates are a hallmark of neurodegenerative disease. Previous work indicates that specific protein components of these aggregates are toxic, including tau (encoded by MAPT) in Alzheimer's disease and related tauopathies. Increasing evidence also indicates that these toxic proteins traffic between cells in a prion-like fashion, thereby spreading pathology from one brain region to another. However, the mechanisms involved in trafficking are poorly understood. We therefore developed a transgenic Drosophila model to facilitate rapid evaluation of candidate tau trafficking modifiers. Our model uses the bipartite Q system to drive co-expression of tau and GFP in the fly eye. We found age-dependent spread of tau into the brain, represented by detection of tau, but not of GFP. We also found that tau trafficking was attenuated upon inhibition of the endocytic factor dynamin (encoded by shi) or knockdown of glycogen synthase kinase-3β (GSK-3β, encoded by sgg). Further work revealed that dynamin promoted tau uptake in recipient tissues, whereas GSK-3β appeared to promote tau spread via direct phosphorylation of tau. Our robust and flexible system will promote the identification of tau-trafficking components involved in the pathogenesis of neurodegenerative diseases.
脑蛋白聚集体是神经退行性疾病的标志。以前的研究表明,这些聚集体中的特定蛋白质成分具有毒性,包括阿尔茨海默病和相关的牛磺酸病中的牛磺酸(由 MAPT 编码)。越来越多的证据还表明,这些有毒蛋白质会以类似朊病毒的方式在细胞间迁移,从而将病变从一个脑区扩散到另一个脑区。然而,人们对其贩运机制知之甚少。因此,我们开发了一种转基因果蝇模型,以便快速评估候选的 tau 转运调节剂。我们的模型使用双Q系统来驱动tau和GFP在果蝇眼睛中的共同表达。我们发现,tau向大脑的扩散与年龄有关,表现为检测到tau,而不是GFP。我们还发现,在抑制内细胞因子达因明(由 shi 编码)或敲除糖原合酶激酶-3β(由 sgg 编码的 GSK-3β)时,tau 的迁移会减弱。进一步的研究发现,达纳明促进了受体组织对 tau 的吸收,而 GSK-3β 似乎通过直接磷酸化 tau 来促进 tau 的扩散。我们的系统既稳健又灵活,将有助于鉴定神经退行性疾病发病机制中的tau-trafficking成分。
期刊介绍:
Disease Models & Mechanisms (DMM) is an online Open Access journal focusing on the use of model systems to better understand, diagnose and treat human disease.