Non-human primate model of amyotrophic lateral sclerosis with cytoplasmic mislocalization of TDP-43.
Non-human primate model of amyotrophic lateral sclerosis with cytoplasmic mislocalization of TDP-43.
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DOI：
10.1093/brain/awr348
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发表时间：
2012-03
期刊：
影响因子：
--
通讯作者：
Yokota T
中科院分区：
文献类型：
--
作者：
Uchida A;Sasaguri H;Kimura N;Tajiri M;Ohkubo T;Ono F;Sakaue F;Kanai K;Hirai T;Sano T;Shibuya K;Kobayashi M;Yamamoto M;Yokota S;Kubodera T;Tomori M;Sakaki K;Enomoto M;Hirai Y;Kumagai J;Yasutomi Y;Mochizuki H;Kuwabara S;Uchihara T;Mizusawa H;Yokota T
肌萎缩侧索硬化症是一种以进行性运动神经元缺失为特征的致死性神经退行性疾病。反式反应脱氧核糖核酸结合蛋白43从细胞核到细胞质的重新分布和胱抑素C阳性Bunina小体的存在被认为是肌萎缩侧索硬化症的病理标志，但其意义尚未完全阐明。由于所有报道的使用野生型反式反应脱氧核糖核酸结合蛋白43的啮齿动物转基因模型未能概括这些特征，我们预期存在种属差异，并旨在制作肌萎缩侧索硬化症的非人灵长类动物模型。我们通过将腺相关病毒载体注射到食蟹猴和大鼠的颈髓中，在脊髓中过表达野生型人反式反应脱氧核糖核酸结合蛋白43，并使用行为学、电生理学、神经病理学和生化分析来检查表型。这些猴子首先出现进行性运动无力和肌肉萎缩，伴有远端手部肌肉的肌束震颤。他们还显示区域性胞质反式反应脱氧核糖核酸结合蛋白43定位错误，神经支配远端手部肌肉的脊髓侧核组中的核反式反应脱氧核糖核酸结合蛋白43染色丢失，以及胱抑素C阳性胞质聚集体，这让人想起肌萎缩侧索硬化症患者的脊髓病理学。反式反应脱氧核糖核酸结合蛋白43的错误定位是一个早期或先兆事件，后来与神经元损失。这些结果表明，反式反应脱氧核糖核酸结合蛋白43的错误定位导致α-运动神经元变性。此外，截短的反式反应脱氧核糖核酸结合蛋白43不是运动神经元变性的先决条件，和磷酸化的反式反应脱氧核糖核酸结合蛋白43发生后，变性已经开始。相反，同样制备的大鼠模型表达的反式反应脱氧核糖核酸结合蛋白43只在运动神经元的核。因此，在反式反应脱氧核糖核酸结合蛋白43病理学中存在种属差异，并且我们的猴模型比啮齿动物模型更大程度地再现了肌萎缩侧索硬化症的病理学，为研究散发性肌萎缩侧索硬化症的发病机制提供了有价值的工具。
Amyotrophic lateral sclerosis is a fatal neurodegenerative disease characterized by progressive motoneuron loss. Redistribution of transactive response deoxyribonucleic acid-binding protein 43 from the nucleus to the cytoplasm and the presence of cystatin C-positive Bunina bodies are considered pathological hallmarks of amyotrophic lateral sclerosis, but their significance has not been fully elucidated. Since all reported rodent transgenic models using wild-type transactive response deoxyribonucleic acid-binding protein 43 failed to recapitulate these features, we expected a species difference and aimed to make a non-human primate model of amyotrophic lateral sclerosis. We overexpressed wild-type human transactive response deoxyribonucleic acid-binding protein 43 in spinal cords of cynomolgus monkeys and rats by injecting adeno-associated virus vector into the cervical cord, and examined the phenotype using behavioural, electrophysiological, neuropathological and biochemical analyses. These monkeys developed progressive motor weakness and muscle atrophy with fasciculation in distal hand muscles first. They also showed regional cytoplasmic transactive response deoxyribonucleic acid-binding protein 43 mislocalization with loss of nuclear transactive response deoxyribonucleic acid-binding protein 43 staining in the lateral nuclear group of spinal cord innervating distal hand muscles and cystatin C-positive cytoplasmic aggregates, reminiscent of the spinal cord pathology of patients with amyotrophic lateral sclerosis. Transactive response deoxyribonucleic acid-binding protein 43 mislocalization was an early or presymptomatic event and was later associated with neuron loss. These findings suggest that the transactive response deoxyribonucleic acid-binding protein 43 mislocalization leads to α-motoneuron degeneration. Furthermore, truncation of transactive response deoxyribonucleic acid-binding protein 43 was not a prerequisite for motoneuronal degeneration, and phosphorylation of transactive response deoxyribonucleic acid-binding protein 43 occurred after degeneration had begun. In contrast, similarly prepared rat models expressed transactive response deoxyribonucleic acid-binding protein 43 only in the nucleus of motoneurons. There is thus a species difference in transactive response deoxyribonucleic acid-binding protein 43 pathology, and our monkey model recapitulates amyotrophic lateral sclerosis pathology to a greater extent than rodent models, providing a valuable tool for studying the pathogenesis of sporadic amyotrophic lateral sclerosis.
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DOI：
10.1111/j.1440-1789.2009.01091.x
发表时间：
2010-04
期刊：
Neuropathology : official journal of the Japanese Society of Neuropathology
影响因子：
--
作者：
Geser F;Lee VM;Trojanowski JQ
通讯作者：
Trojanowski JQ
影响因子：
3.5
作者：
Ash, Peter E. A.;Zhang, Yong-Jie;Link, Christopher D.
通讯作者：
Link, Christopher D.
影响因子：
14.5
作者：
HAVERKAMP, LJ;APPEL, V;APPEL, SH
通讯作者：
APPEL, SH
影响因子：
6
作者：
Cairns, Nigel J.;Neumann, Manuela;Mackenzie, Ian R. A.
通讯作者：
Mackenzie, Ian R. A.
影响因子：
5.4
作者：
Buratti, Emanuele;De Conti, Laura;Baralle, Francisco
通讯作者：
Baralle, Francisco