TDP43 在细胞质中的聚集与 rTg4510 小鼠 tau 病模型中 tau 和 α-突触核蛋白积累的地形相关性。

Cytoplasmic aggregation of TDP43 and topographic correlation with tau and α-synuclein accumulation in the rTg4510 mouse model of tauopathy.

机构信息

Laboratory of Veterinary Pathology, Graduate School of Agricultural and Life Science, The University of Tokyo, Tokyo, Japan.

出版信息

J Neuropathol Exp Neurol. 2024 Oct 1;83(10):833-842. doi: 10.1093/jnen/nlae063.

DOI:10.1093/jnen/nlae063

PMID:38879441

Abstract

In patients with TDP43 proteinopathy, phosphorylated TDP43 (p-TDP43) accumulates in the cytoplasm of neurons. The accumulation of p-TDP43 has also been reported in patients with tauopathy and α-synucleinopathy. We investigated spatiotemporal changes in p-TDP43 accumulation in the brains of rTg4510 mice that overexpressed human mutant tau (P301L) and exhibited hyperphosphorylated tau (hp-tau) and phosphorylated αSyn (p-αSyn) accumulation. Immunohistochemically, p-TDP43 aggregates were observed in the cytoplasm of neurons, which increased with age. A significant positive correlation was observed between the number of cells with p-TDP43 aggregates and hp-tau and p-αSyn aggregates. Suppression of the human mutant tau (P301L) expression by doxycycline treatment reduces the accumulation of p-TDP43, hp-tau, and p-αSyn. Proteinase K-resistant p-TDP43 aggregates were found in regions with high hp-tau, and p-αSyn accumulation. Western blotting of the sarkosyl-insoluble fraction revealed bands of monomeric TDP43 and p-TDP43. These results indicate that the accumulation of mouse p-TDP43 is associated with the accumulation of human mutant tau (P301L) in rTg4510 mouse brains. The accumulation of hp-tau and p-αSyn may promote sarkosyl-insoluble p-TDP43 aggregates that are resistant to proteinase K. The synergistic effects of tau, TDP43, and αSyn may be involved in the pathology of proteinopathies, leading to the accumulation of multiple abnormal proteins.

摘要

在 TDP43 蛋白病患者中，磷酸化 TDP43（p-TDP43）在神经元的细胞质中积累。磷酸化 TDP43 的积累也在tau 病和α-突触核蛋白病患者中报道过。我们研究了过表达人突变型 tau（P301L）并表现出过度磷酸化 tau（hp-tau）和磷酸化αSyn（p-αSyn）积累的 rTg4510 小鼠大脑中 p-TDP43 积累的时空变化。免疫组织化学染色显示，p-TDP43 聚集体出现在神经元的细胞质中，随着年龄的增长而增加。p-TDP43 聚集体的细胞数量与 hp-tau 和 p-αSyn 聚集体之间存在显著的正相关。用强力霉素处理抑制人突变型 tau（P301L）的表达可减少 p-TDP43、hp-tau 和 p-αSyn 的积累。在高 hp-tau 和 p-αSyn 积累的区域发现了对蛋白酶 K 有抗性的 p-TDP43 聚集体。 Sarkosyl 不溶性级分的 Western blot 显示单体 TDP43 和 p-TDP43 的条带。这些结果表明，rTg4510 小鼠大脑中 p-TDP43 的积累与人突变型 tau（P301L）的积累有关。hp-tau 和 p-αSyn 的积累可能促进 Sarkosyl 不溶性 p-TDP43 聚集体的形成，这些聚集体对蛋白酶 K 有抗性。tau、TDP43 和αSyn 的协同作用可能参与了蛋白病的病理学，导致多种异常蛋白的积累。