Age-related motor neuron degeneration in DNA repair-deficient Ercc1 mice.
Age-related motor neuron degeneration in DNA repair-deficient Ercc1 mice.
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DOI：
10.1007/s00401-010-0715-9
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发表时间：
2010-10
影响因子：
12.7
通讯作者：
Jaarsma D
中科院分区：
文献类型：
--
作者：
de Waard MC;van der Pluijm I;Zuiderveen Borgesius N;Comley LH;Haasdijk ED;Rijksen Y;Ridwan Y;Zondag G;Hoeijmakers JH;Elgersma Y;Gillingwater TH;Jaarsma D
运动神经元的退化导致与衰老相关的肌肉功能丧失，是肌萎缩性侧索硬化症和脊髓性肌萎缩症等人类神经退行性疾病的基础。因此，鉴定导致运动神经元易感性和体内退行性表型的遗传因素对于我们理解健康和疾病中的神经肌肉系统非常重要。在这里，我们分析了在几种DNA修复系统中受损的类早衰Ercc1 Δ/−小鼠脊髓中的神经退行性异常，即核苷酸切除修复、链间交联修复和双链断裂修复。Ercc1 Δ/ -小鼠出现年龄依赖性运动异常，寿命缩短6-7个月。病理上，Ercc1 Δ/−小鼠出现广泛的星形细胞增生和小胶质细胞增生，运动神经元丢失和骨骼肌纤维去神经支配。退行性运动神经元在许多情况下表达基因毒性反应转录因子p53或ATF3，此外，还表现出一系列高尔基体异常。此外，Ercc1 Δ/−运动神经元出现核周和轴突中间丝异常，令人想起在衰老脊髓中观察到的细胞骨骼病理。我们的研究结果支持这样一种观点，即DNA损伤和基因毒性应激的积累可能导致人类神经肌肉疾病中的神经元老化和运动神经元易感性。本文的在线版本（doi:10.1007/s00401-010-0715-9）包含补充材料，授权用户可以使用。
Degeneration of motor neurons contributes to senescence-associated loss of muscle function and underlies human neurodegenerative conditions such as amyotrophic lateral sclerosis and spinal muscular atrophy. The identification of genetic factors contributing to motor neuron vulnerability and degenerative phenotypes in vivo are therefore important for our understanding of the neuromuscular system in health and disease. Here, we analyzed neurodegenerative abnormalities in the spinal cord of progeroid Ercc1 Δ/− mice that are impaired in several DNA repair systems, i.e. nucleotide excision repair, interstrand crosslink repair, and double strand break repair. Ercc1 Δ/− mice develop age-dependent motor abnormalities, and have a shortened life span of 6–7 months. Pathologically, Ercc1 Δ/− mice develop widespread astrocytosis and microgliosis, and motor neuron loss and denervation of skeletal muscle fibers. Degenerating motor neurons in many occasions expressed genotoxic-responsive transcription factors p53 or ATF3, and in addition, displayed a range of Golgi apparatus abnormalities. Furthermore, Ercc1 Δ/− motor neurons developed perikaryal and axonal intermediate filament abnormalities reminiscent of cytoskeletal pathology observed in aging spinal cord. Our findings support the notion that accumulation of DNA damage and genotoxic stress may contribute to neuronal aging and motor neuron vulnerability in human neuromuscular disorders. The online version of this article (doi:10.1007/s00401-010-0715-9) contains supplementary material, which is available to authorized users.
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影响因子：
56.9
作者：
Houtsmuller, AB;Rademakers, S;Vermeulen, W
通讯作者：
Vermeulen, W
影响因子：
--
作者：
Coppede, Fabio;Migheli, Francesca;Migliore, Lucia
通讯作者：
Migliore, Lucia
影响因子：
9.8
作者：
Chen, YZ;Bennett, CL;Chance, PF
通讯作者：
Chance, PF
DOI：
10.1083/jcb.119.3.493
发表时间：
1992-11
期刊：
The Journal of cell biology
影响因子：
--
作者：
Gavrieli Y;Sherman Y;Ben-Sasson SA
通讯作者：
Ben-Sasson SA
影响因子：
4.4
作者：
Gonatas, Nicholas K.;Stieber, Anna;Gonatas, Jacqueline O.
通讯作者：
Gonatas, Jacqueline O.