Muscle-dominant wild-type TDP-43 expression induces myopathological changes featuring tubular aggregates and TDP-43-positive inclusions
Muscle-dominant wild-type TDP-43 expression induces myopathological changes featuring tubular aggregates and TDP-43-positive inclusions
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肌肉主导的野生型 TDP-43 表达诱导以管状聚集体和 TDP-43 阳性包涵体为特征的肌病理学变化
DOI：
10.1016/j.expneurol.2018.08.006
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发表时间：
2018
影响因子：
5.3
通讯作者：
Ando Yukio
中科院分区：
文献类型：
--
作者：
Tawara Nozomu;Yamashita Satoshi;Kawakami Kensuke;Kurashige Takashi;Zhang Ziwei;Tasaki Masayoshi;Yamamoto Yasuhiro;Nishikami Tomo;Doki Tsukasa;Zhang Xiao;Matsuo Yoshimasa;Kimura En;Tawara Akie;Maeda Yasushi;Hauschka Stephen D.;Maruyama Hirofumi;Ando Yukio
散发性包涵体肌炎（sIBM）的肌肉组织学表现出炎性发现和退行性特征，包括43 kDa TAR DNA结合蛋白（TDP-43）的积累。然而，TDP-43的肌浆蓄积是否是sIBM病理生理学中肌肉变性的主要触发因素或由肌肉变性引起的次要事件仍不清楚。我们的研究旨在发现TDP-43的肌肉显性表达是否是肌肉变性的主要原因。我们产生了几个线的野生型TDP-43转基因小鼠驱动的肌酸激酶8启动子，并通过生物化学，组织学和蛋白质组学技术分析的表型。小鼠的血清生肌酶水平升高。肌肉组织学显示肌病变化，包括纤维大小变化、丰富的管状聚集体和TDP-43聚集，以及内质网（ER）应激上调。对变性肌纤维中聚集材料的蛋白质组学分析鉴定了增加的调节钙稳态的肌浆网（SR）/ER驻留蛋白，以及细胞溶质5′-核苷酸酶1A。肌肉优势野生型TDP-43表达确实引起了以管状聚集体和TDP-43阳性包涵体为特征的肌毒性，我们的观察表明，TDP-43聚集体可能不足以触发sIBM的发病机制，尽管TDP-43的肌纤维肌浆聚集通过ER应激和可能的钙调节失调导致肌纤维变性，而与炎症过程无关。
Muscle histology of sporadic inclusion body myositis (sIBM) demonstrates inflammatory findings and degenerative features including accumulation of TAR DNA-binding protein of 43 kDa (TDP-43). However, whether sarcoplasmic accumulation of TDP-43 is a primary trigger of muscle degeneration or a secondary event resulting from muscle degeneration in the pathophysiology of sIBM remained unclear. Our study aimed to discover whether muscle-dominant expression of TDP-43 is a primary cause of muscle degeneration. We generated several lines of wild-type TDP-43 transgenic mice driven by a creatine kinase 8 promoter, and analyzed the phenotypes via biochemical, histological, and proteomic techniques. The mice showed increased serum levels of myogenic enzymes. Muscle histology demonstrated myopathic changes including fiber size variation, abundant tubular aggregates, and TDP-43 aggregation with upregulation of endoplasmic reticulum (ER) stress. Proteomic analysis with aggregated materials in degenerative myofibers identified increased sarcoplasmic reticulum (SR)/ER-resident proteins that regulated calcium homeostasis, as well as cytosolic 5′-nucleotidase 1A. Muscle-dominant wild-type TDP-43 expression indeed caused myotoxicity featuring tubular aggregates and TDP-43-positive inclusions.Our observation suggested that TDP-43 aggregates might not be sufficient to trigger the pathogenesis of sIBM although myofiber sarcoplasmic aggregation of TDP-43 led to myofiber degeneration via ER stress and possibly calcium dysregulation, independently of inflammatory process.
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影响因子：
14.5
作者：
Benveniste, Olivier;Guiguet, Marguerite;Hilton-Jones, David
通讯作者：
Hilton-Jones, David
影响因子：
1.2
作者：
Nakanishi, Hirotaka;Koike, Haruki;Sobue, Gen
通讯作者：
Sobue, Gen
影响因子：
5
作者：
S. Yamashita;E. Kimura;N. Tawara;H. Sakaguchi;T. Nakama;Y. Maeda;T. Hirano;M. Uchino;Y. Ando
通讯作者：
S. Yamashita;E. Kimura;N. Tawara;H. Sakaguchi;T. Nakama;Y. Maeda;T. Hirano;M. Uchino;Y. Ando
DOI：
--
发表时间：
2014
期刊：
Journal of the Neurological Sciences.
影响因子：
--
作者：
Hori H;Yamashita S;Tawara N;Hirahara T;Kawakami K;Nishikami T;Maeda Y;Ando Y
通讯作者：
Ando Y
DOI：
10.1016/j.bbrc.2006.10.093
发表时间：
2006-12-22
影响因子：
3.1
作者：
Arai, Tetsuaki;Hasegawa, Masato;Oda, Tatsuro
通讯作者：
Oda, Tatsuro