Study on involvement of of tau-binding factors in neurodegeneration

神经原纤维缠结是阿尔茨海默病(AD)和其他神经病变的神经病理特征，包括额颞叶痴呆(FTD)和皮质基底膜变性，异常过度磷酸化的tau蛋白是NFT的主要蛋白质成分。自从发现17号染色体上的tau基因是家族性FTD(FTDP-17)的致病基因后，tau基因被认为对了解痴呆的神经退变过程具有重要意义。在tauopathy的脑组织中，tau被过度磷酸化和泛素化，并自组装形成细丝或聚集体，但tau参与神经变性的机制尚不清楚。为了了解tau的自组装机制，我们研究了tau的磷酸化对14-3-3诱导的自组装过程的影响。蛋白激酶A(PKA)或蛋白激酶B(PKB)对tau蛋白的磷酸化增强了tau蛋白与14-3-3的结合，而不是糖原合成酶-3，但PKA或PKB磷酸化抑制了tau蛋白的自组装。我们还研究了tau基因FTDP-17突变对14-3-3诱导的自组装过程的影响。突变体tau(P301L、V337M和R406W)与14-3-3的亲和力高于野生型tau，且在14-3-3存在时，P301L tau诱导的自组装水平最高。我们的结果表明，tau的磷酸化和突变可能在tau的自组装过程中发挥重要作用。

Neurofibrillary tangles are neuropathological hallmarks of Alzheimer disease (AD) and other tauopathies including frontotemporal dementia (FTD) and corticobasal degeneration, and abnormally hyperphosphorylated tau protein is the major protein component of NFT. After finding of tau gene on chromosome 17 as a causative gene for familial FTD (FTDP-17), tau is thought to be essentially important for understanding of neurodegenerative processes in dementia. In brain of tauopathies tau is hyperphosphorylated and ubiquitinated, and self-assembles and forms filaments or aggregates, however the mechanisms of the involvement of tau in neurodegeneration are unclear.To understand the mechanisms of self-assembly of tau, we investigated the effects of phosphorylation of tau on the process self-assembly induced by 14-3-3. Phosphorylation of tau by protein kinase A (PKA) or protein kinase B (PKB), not glycogen synthase kinase-3, enhanced the binding of tau with 14-3-3, however PKA- or PKB-phosphorylation abolished the self-assembly of tau protein. And we investigated the effects of FTDP-17 mutations of tau on the process self-assembly induced by 14-3-3. The mutant tau (P301L, V337M and R406W) had higher affinity with 14-3-3 than wild type tau, and P301L tau induced the highest self-assembly level than others in the presence of 14-3-3. Our results suggest that phosphorylation and mutations of tau might play an important role in self-assembly of tau.