TIA1 regulates the generation and response to toxic tau oligomers
TIA1 regulates the generation and response to toxic tau oligomers
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DOI：
10.1007/s00401-018-1937-5
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发表时间：
2019-02-01
影响因子：
12.7
通讯作者：
Wolozin, Benjamin
中科院分区：
文献类型：
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作者：
Jiang, Lulu;Ash, Peter E. A.;Wolozin, Benjamin
RNA结合蛋白（RBP）与运动神经元疾病的病理生理学密切相关。最近的研究表明，RBP，如TIA1，也有助于tau蛋白病的病理生理学。RBP与tau病理学共定位，并且TIA1的减少防止tau介导的神经变性。TIA1减少防止tau蛋白病的机制以及TIA1是否调节tau蛋白的传播尚不清楚。先前的研究表明，TIA1耗竭的保护作用与寡聚tau的减少和病理性TIA1阳性tau包涵体的减少相关。在目前的报告中，我们使用了一种新的tau繁殖方法来测试TIA1是否是产生有毒tau寡聚体所必需的，以及TIA1的减少是否会防止这些寡聚体的扩散。该方法使用年轻的PS19 P301 S tau小鼠，在该年龄通常还不会发生神经变性，并通过注射到海马CA1区来接种寡聚体或纤维状tau。我们发现，在这个模型中，外源性tau寡聚体（而不是原纤维）在大脑中的传播驱动神经变性。我们证明，TIA1减少基本上括号的病理生理学的tau，需要生产的tau寡聚体，以及调节神经元的反应繁殖有毒的tau寡聚体。这些结果表明，RNA结合蛋白在多个水平上调节tau的病理生理学，并提供了对可能的治疗方法的见解，以减少tau蛋白病中神经变性的传播。
RNA binding proteins (RBPs) are strongly linked to the pathophysiology of motor neuron diseases. Recent studies show that RBPs, such as TIA1, also contribute to the pathophysiology of tauopathy. RBPs co-localize with tau pathology, and reduction of TIA1 protects against tau-mediated neurodegeneration. The mechanism through which TIA1 reduction protects against tauopathy, and whether TIA1 modulates the propagation of tau, are unknown. Previous studies indicate that the protective effect of TIA1 depletion correlates with both the reduction of oligomeric tau and the reduction of pathological TIA1 positive tau inclusions. In the current report, we used a novel tau propagation approach to test whether TIA1 is required for producing toxic tau oligomers and whether TIA1 reduction would provide protection against the spread of these oligomers. The approach used young PS19 P301S tau mice at an age at which neurodegeneration would normally not yet occur and seeding oligomeric or fibrillar tau by injection into hippocampal CA1 region. We find that propagation of exogenous tau oligomers (but not fibrils) across the brain drives neurodegeneration in this model. We demonstrate that TIA1 reduction essentially brackets the pathophysiology of tau, being required for the production of tau oligomers, as well as regulating the response of neurons to propagated toxic tau oligomers. These results indicate that RNA binding proteins modulate the pathophysiology of tau at multiple levels and provide insights into possible therapeutic approaches to reduce the spread of neurodegeneration in tauopathy.