Miyasaka Tomohiro, Shinzaki Yuki, Yoshimura Satomi, Yoshina Sawako, Kage-Nakadai Eriko, Mitani Shohei, Ihara Yasuo
Department of Neuropathology, Faculty of Life and Medical Sciences, Doshisha University, Kyoto, Japan.
Department of Physiology, School of Medicine, Tokyo Women's Medical University, Tokyo, Japan.
Front Neurosci. 2018 Jun 20;12:415. doi: 10.3389/fnins.2018.00415. eCollection 2018.
Tauopathy is a type of dementia defined by the accumulation of filamentous tau inclusions in neural cells. Most types of dementia in the elderly, including Alzheimer's disease, are tauopathies. Although it is believed that tau protein abnormalities and/or the loss of its functions results in neurodegeneration and dementia, the mechanism of tauopathy remains obscure. Loss of microtubules and/or tubulin is a known consequence of tau accumulating in neurons in Alzheimer's disease. In other words, there is an excess level of tau relative to tubulin in tauopathy neurons. To test whether this imbalance of tau and tubulin expression results in the neurotoxicity of tau, we developed several transgenic lines that express human tau at various levels in pan-neurons. These worms showed behavioral abnormalities in a tau expression-dependent manner. The knockdown of a tubulin-specific chaperon, or a subset of tubulin, led to enhanced tau toxicity even in low-expressing tau-transgenic worms that showed no abnormal behaviors. In addition, the suppression of tau expression in tubulin knockdown worms rescued neuronal dysfunction. Thus, not only the overexpression of tau but also a reduction in tubulin can trigger the neurotoxicity of tau. Tau expressed in worms was also highly phosphorylated and largely bound to tubulin dimers rather than microtubules. Relative amount of tubulin-unbound tau was increased in high-expressing tau-transgenic worms showing tau toxicity. We further demonstrated that tau aggregation was inhibited by co-incubation of purified tubulin , meaning sufficient amounts of tubulin can protect against the formation of tau inclusions. These results suggest that the expression ratio of tau to tubulin may be a determinant of the tauopathy cascade.
tau蛋白病是一种痴呆症，其定义为神经细胞中丝状tau包涵体的积累。大多数老年痴呆症类型，包括阿尔茨海默病，都是tau蛋白病。尽管人们认为tau蛋白异常和/或其功能丧失会导致神经退行性变和痴呆，但tau蛋白病的发病机制仍不清楚。微管和/或微管蛋白的丧失是阿尔茨海默病中tau蛋白在神经元中积累的已知后果。换句话说，在tau蛋白病神经元中，相对于微管蛋白，tau蛋白水平过高。为了测试tau蛋白和微管蛋白表达的这种失衡是否会导致tau蛋白的神经毒性，我们开发了几个在全神经元中以不同水平表达人类tau蛋白的转基因品系。这些线虫表现出tau蛋白表达依赖性的行为异常。敲低微管蛋白特异性伴侣蛋白或微管蛋白的一个子集，即使在没有异常行为的低表达tau转基因线虫中，也会导致tau蛋白毒性增强。此外，在敲低微管蛋白的线虫中抑制tau蛋白表达可挽救神经元功能障碍。因此，不仅tau蛋白的过表达，而且微管蛋白的减少都能引发tau蛋白的神经毒性。在线虫中表达的tau蛋白也高度磷酸化，并且主要与微管蛋白二聚体结合，而不是与微管结合。在表现出tau蛋白毒性的高表达tau转基因线虫中，未与微管蛋白结合的tau蛋白相对量增加。我们进一步证明，纯化的微管蛋白共同孵育可抑制tau蛋白聚集，这意味着足够量的微管蛋白可以防止tau蛋白包涵体的形成。这些结果表明，tau蛋白与微管蛋白的表达比例可能是tau蛋白病级联反应的一个决定因素。
