Phosphorylation of Tau at Threonine 231 in Patients With Multiple System Atrophy and in a Mouse Model
Phosphorylation of Tau at Threonine 231 in Patients With Multiple System Atrophy and in a Mouse Model
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多系统萎缩患者和小鼠模型中 Tau 苏氨酸 231 的磷酸化
DOI：
10.1093/jnen/nlac082
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发表时间：
2022
期刊：
影响因子：
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通讯作者：
Wakabayashi Koichi
中科院分区：
文献类型：
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作者：
Tanaka Makoto T;Tanji Kunikazu;Miki Yasuo;Ozaki Taku;Mori Fumiaki;Hayashi Hideki;Kakita Akiyoshi;Wakabayashi Koichi
多系统萎缩（MSA）是一种散发性神经退行性疾病，其病理学特征是存在神经胶质细胞质内含物（GCI）。一些 MSA 患者表现出运动缺陷并伴有认知障碍。值得注意的是，一些病程较长的 MSA 患者存在 AT8 阳性信号，对应于 202/205 处的磷酸化 tau (P-tau) (P-tau202/205)。然而，除 AT8 抗体表位抗体之外的 P-tau 位点研究较少。在这里，我们重点研究了 MSA 模型小鼠中 α-突触核蛋白 (Syn) 表达对 tau 磷酸化的影响。在6种抗P-tau抗体中，我们证实了抗P-tau 231抗体（P-tau231）具有磷酸特异性，并发现P-tau231水平在MSA模型小鼠中与疾病进展平行增加。对人脑的进一步研究表明，P-tau231 主要在 MSA 大脑的颞叶皮层表达，且其表达水平在 MSA 患者中显着高于对照组。免疫组织化学分析显示，抗P-tau231-而非AT8抗体主要免疫标记海马CA2/3锥体神经元以及MSA中的一些GCI。这些数据表明 P-tau231 在 MSA 中的发生方式与 P-tau202/205 不同。
Multiple system atrophy (MSA) is a sporadic neurodegenerative disorder pathologically characterized by the presence of glial cytoplasmic inclusions (GCIs). Some MSA patients exhibit motor deficits with accompanying cognitive impairment. Of note, some patients suffering from MSA with longer disease duration have AT8-positive signals, which correspond to phosphorylated tau (P-tau) at 202/205 (P-tau202/205). However, P-tau sites other than the AT8 antibody epitope antibody are less well studied. Here, we focused on the effect of α-synuclein (Syn) expression on the phosphorylation of tau in MSA model mice. Among the 6 kinds of antibodies against P-tau, we confirmed that antibodies against P-tau at 231 (P-tau231) were phospho-specific and found that P-tau231 level was increased in parallel with disease progression in MSA model mice. Additional studies of human brains revealed that P-tau231 was mainly expressed in the temporal cortex in MSA brains and that its expression level was significantly higher in MSA patients than in controls. Immunohistochemical analysis showed that anti-P-tau231-, but not AT8, antibodies mainly immunolabeled hippocampal CA2/3 pyramidal neurons, and some GCIs in MSA. These data suggest that P-tau231 occurs in MSA differently from P-tau202/205.