Drosophila TDP-43 dysfunction in glia and muscle cells cause cytological and behavioural phenotypes that characterize ALS and FTLD.
Drosophila TDP-43 dysfunction in glia and muscle cells cause cytological and behavioural phenotypes that characterize ALS and FTLD.
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DOI：
10.1093/hmg/ddt243
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发表时间：
2013-10-01
影响因子：
3.5
通讯作者：
Hirth F
中科院分区：
文献类型：
--
作者：
Diaper DC;Adachi Y;Lazarou L;Greenstein M;Simoes FA;Di Domenico A;Solomon DA;Lowe S;Alsubaie R;Cheng D;Buckley S;Humphrey DM;Shaw CE;Hirth F
肌萎缩侧索硬化症（ALS）和额颞叶变性（FTLD）是以TAR DNA结合蛋白43（TDP-43）的细胞质聚集和细胞核清除为特征的神经退行性疾病。在果蝇、斑马鱼和小鼠中的研究表明，TDP-43的神经元功能障碍与疾病形成有因果关系。然而，在ALS和FTLD中同样受到影响的神经胶质和肌肉细胞中也观察到TDP-43聚集体;然而，目前尚不清楚TDP-43的神经胶质或肌肉特异性功能障碍是否有助于发病机制。在这里，我们表明，类似于其人类同源物，果蝇TDP-43，焦油DNA结合蛋白同源物（TBPH），在神经胶质细胞和肌肉细胞中表达。TBPH的肌肉特异性敲低导致与年龄相关的运动异常，而肌肉特异性功能获得导致肌浆聚集和核TBPH耗竭，这伴随着行为缺陷和过早致死。神经胶质细胞中的TBPH功能障碍导致与年龄相关的运动缺陷和过早死亡。此外，果蝇TDP-43的丢失和获得都会改变谷氨酸转运蛋白兴奋性氨基酸转运蛋白1（EAAT 1）和EAAT 2的mRNA表达水平。综上所述，我们的研究结果表明，TDP-43在肌肉和神经胶质细胞中功能的丧失和获得都可以导致果蝇的细胞学和行为表型，这些表型也表征ALS和FTLD，并将谷氨酸转运蛋白EAAT 1/2鉴定为TDP-43功能的潜在直接靶点。这些发现表明，与神经元病理学一起，神经胶质和肌肉特异性TDP-43功能障碍可能直接导致TDP-43相关ALS和FTLD的病因和进展。
Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are neurodegenerative disorders that are characterized by cytoplasmic aggregates and nuclear clearance of TAR DNA-binding protein 43 (TDP-43). Studies in Drosophila, zebrafish and mouse demonstrate that the neuronal dysfunction of TDP-43 is causally related to disease formation. However, TDP-43 aggregates are also observed in glia and muscle cells, which are equally affected in ALS and FTLD; yet, it is unclear whether glia- or muscle-specific dysfunction of TDP-43 contributes to pathogenesis. Here, we show that similar to its human homologue, Drosophila TDP-43, Tar DNA-binding protein homologue (TBPH), is expressed in glia and muscle cells. Muscle-specific knockdown of TBPH causes age-related motor abnormalities, whereas muscle-specific gain of function leads to sarcoplasmic aggregates and nuclear TBPH depletion, which is accompanied by behavioural deficits and premature lethality. TBPH dysfunction in glia cells causes age-related motor deficits and premature lethality. In addition, both loss and gain of Drosophila TDP-43 alter mRNA expression levels of the glutamate transporters Excitatory amino acid transporter 1 (EAAT1) and EAAT2. Taken together, our results demonstrate that both loss and gain of TDP-43 function in muscle and glial cells can lead to cytological and behavioural phenotypes in Drosophila that also characterize ALS and FTLD and identify the glutamate transporters EAAT1/2 as potential direct targets of TDP-43 function. These findings suggest that together with neuronal pathology, glial- and muscle-specific TDP-43 dysfunction may directly contribute to the aetiology and progression of TDP-43-related ALS and FTLD.
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影响因子：
16.2
作者：
Ash PE;Bieniek KF;Gendron TF;Caulfield T;Lin WL;Dejesus-Hernandez M;van Blitterswijk MM;Jansen-West K;Paul JW 3rd;Rademakers R;Boylan KB;Dickson DW;Petrucelli L
通讯作者：
Petrucelli L
影响因子：
38.1
作者：
Chen-Plotkin, Alice S.;Lee, Virginia M. -Y.;Trojanowski, John Q.
通讯作者：
Trojanowski, John Q.
影响因子：
2.3
作者：
Gitler, Aaron D.;Shorter, James
通讯作者：
Shorter, James
影响因子：
2.5
作者：
Flomen, Rachel;Makoff, Andrew
通讯作者：
Makoff, Andrew
影响因子：
5.7
作者：
Da Cruz S;Cleveland DW
通讯作者：
Cleveland DW