Tau isoform expression and phosphorylation in marmoset brains
Tau isoform expression and phosphorylation in marmoset brains
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DOI：
10.1074/jbc.ra119.008415
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发表时间：
2019-06
期刊：
影响因子：
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通讯作者：
Govinda Sharma;Anni Huo;Taeko Kimura;Seiji Shiozawa;Reona Kobayashi;N. Sahara;Minaka Ishibashi;S. Ishigaki;Taro Saito;K. Ando;S. Murayama;M. Hasegawa;G. Sobue;H. Okano;S. Hisanaga
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作者：
Govinda Sharma;Anni Huo;Taeko Kimura;Seiji Shiozawa;Reona Kobayashi;N. Sahara;Minaka Ishibashi;S. Ishigaki;Taro Saito;K. Ando;S. Murayama;M. Hasegawa;G. Sobue;H. Okano;S. Hisanaga
Tau是一种在神经元轴突中表达的微管相关蛋白。过度磷酸化的tau是神经原纤维缠结的主要成分，是阿尔茨海默病（AD）的病理标志。在许多神经退行性疾病（统称为“tau病”）中也发现了过度磷酸化的tau聚集体，tau突变与家族性额颞叶变性（FTLD）有关。先前的研究已经产生了带有突变tau的转基因小鼠作为牛头病模型，但与人类更相似的非人类灵长类动物可能是研究牛头病的更好模型。例如，普通狨猴被用作研究与年龄相关的神经退行性疾病的病因学的非人类灵长类动物模型。然而，没有在狨猴大脑中进行tau的生化研究。在这里，我们研究了tau的几个重要方面，包括在狨猴大脑中不同tau亚型的表达及其磷酸化状态。我们发现狨猴tau在其n端结构域不具有“灵长类独有的基序”。我们还发现，与人类相比，狨猴的tau亚型表达模式与小鼠更相似，成年狨猴的大脑与成年小鼠一样只表达四重复tau亚型，而与成年人类的大脑不同。值得注意的是，狨猴新生儿大脑中的tau蛋白在与AD病理相关的几个位点被磷酸化。然而，在成年狨猴的大脑中，除了Ser-202和Ser-404磷酸化外，大部分磷酸化都丢失了。这些结果揭示了狨猴大脑中tau表达和磷酸化的关键特征，这是一种潜在的有用的神经退行性疾病的非人类灵长类动物模型。
Tau is a microtubule-associated protein expressed in neuronal axons. Hyperphosphorylated tau is a major component of neurofibrillary tangles, a pathological hallmark of Alzheimer's disease (AD). Hyperphosphorylated tau aggregates are also found in many neurodegenerative diseases, collectively referred to as “tauopathies,” and tau mutations are associated with familial frontotemporal lobar degeneration (FTLD). Previous studies have generated transgenic mice with mutant tau as tauopathy models, but nonhuman primates, which are more similar to humans, may be a better model to study tauopathies. For example, the common marmoset is poised as a nonhuman primate model for investigating the etiology of age-related neurodegenerative diseases. However, no biochemical studies of tau have been conducted in marmoset brains. Here, we investigated several important aspects of tau, including expression of different tau isoforms and its phosphorylation status, in the marmoset brain. We found that marmoset tau does not possess the “primate-unique motif” in its N-terminal domain. We also discovered that the tau isoform expression pattern in marmosets is more similar to that of mice than that of humans, with adult marmoset brains expressing only four-repeat tau isoforms as in adult mice but unlike in adult human brains. Of note, tau in brains of marmoset newborns was phosphorylated at several sites associated with AD pathology. However, in adult marmoset brains, much of this phosphorylation was lost, except for Ser-202 and Ser-404 phosphorylation. These results reveal key features of tau expression and phosphorylation in the marmoset brain, a potentially useful nonhuman primate model of neurodegenerative diseases.