Mitochondria, ER, and nuclear membrane defects reveal early mechanisms for upper motor neuron vulnerability with respect to TDP-43 pathology
Mitochondria, ER, and nuclear membrane defects reveal early mechanisms for upper motor neuron vulnerability with respect to TDP-43 pathology
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DOI：
10.1007/s00401-018-1934-8
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发表时间：
2019-01-01
影响因子：
12.7
通讯作者：
Ozdinler, P. Hande
中科院分区：
文献类型：
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作者：
Gautam, Mukesh;Jara, Javier H.;Ozdinler, P. Hande
含有TDP-43的不溶性聚集体在病变大脑中被广泛观察到，并被定义为神经退行性疾病谱系中的TDP-43病理学，如肌萎缩侧索硬化症（ALS）、阿尔茨海默病和ALS合并额颞叶痴呆。在这里，我们报告了TDP-43病理患者的Betz细胞显示出一组独特的细胞内缺陷，特别是在核膜，线粒体和内质网（ER）部位。已经建立了许多TDP-43小鼠模型来识别该疾病的细胞和分子基础，但神经元易感性的机制仍然未知。为了确定皮质脊髓运动神经元（CSMN）退化的潜在原因，我们产生了一种新的具有TDP-43病理的CSMN报告系，prp-TDP-43(A315T)-UeGFP小鼠，并对其进行了表征。我们发现TDP-43病理相关的细胞内问题在疾病中很早就出现了。人类的Betz细胞和小鼠的CSMN细胞在TDP-43病理上都有线粒体受损，并表现出核膜和内质网缺陷。
Insoluble aggregates containing TDP-43 are widely observed in the diseased brain, and defined as TDP-43 pathology in a spectrum of neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), Alzheimer's disease and ALS with frontotemporal dementia. Here we report that Betz cells of patients with TDP-43 pathology display a distinct set of intracellular defects especially at the site of nuclear membrane, mitochondria and endoplasmic reticulum (ER). Numerous TDP-43 mouse models have been generated to discern the cellular and molecular basis of the disease, but mechanisms of neuronal vulnerability remain unknown. In an effort to define the underlying causes of corticospinal motor neuron (CSMN) degeneration, we generated and characterized a novel CSMN reporter line with TDP-43 pathology, the prp-TDP-43(A315T)-UeGFP mice. We find that TDP-43 pathology related intracellular problems emerge very early in the disease. The Betz cells in humans and CSMN in mice both have impaired mitochondria, and display nuclear membrane and ER defects with respect to TDP-43 pathology.