p150（黏连蛋白）中的G59S突变导致小鼠动力蛋白激活蛋白功能障碍。
The G59S mutation in p150(glued) causes dysfunction of dynactin in mice.
作者信息
Lai Chen, Lin Xian, Chandran Jayanth, Shim Hoon, Yang Wan-Jou, Cai Huaibin
机构信息
Unit of Transgenesis, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland 20892, USA.
出版信息
J Neurosci. 2007 Dec 19;27(51):13982-90. doi: 10.1523/JNEUROSCI.4226-07.2007.
The G59S missense mutation at the conserved microtubule-binding domain of p150(glued), a major component of dynein/dynactin complex, has been linked to an autosomal dominant form of motor neuron disease (MND). To study how this mutation affects the function of the dynein/dynactin complex and contributes to motor neuron degeneration, we generated p150(glued) G59S knock-in mice. We found that the G59S mutation destabilizes p150(glued) and disrupts the function of dynein/dynactin complex, resulting in early embryonic lethality of homozygous knock-in mice. Heterozygous knock-in mice, which developed normally, displayed MND-like phenotypes after 10 months of age, including excessive accumulation of cytoskeletal and synaptic vesicle proteins at neuromuscular junctions, loss of spinal motor neurons, increase of reactive astrogliosis, and shortening of gait compared with wild-type littermates and age-matched p150(glued) heterozygous knock-out mice. Our findings indicate that the G59S mutation in p150(glued) abrogates the normal function of p150(glued) and accelerates motor neuron degeneration.
动力蛋白/动力蛋白激活蛋白复合物的主要成分p150（glued）的保守微管结合结构域中的G59S错义突变，与常染色体显性形式的运动神经元疾病（MND）有关。为了研究该突变如何影响动力蛋白/动力蛋白激活蛋白复合物的功能并导致运动神经元退化，我们构建了p150（glued）G59S基因敲入小鼠。我们发现，G59S突变使p150（glued）不稳定，并破坏了动力蛋白/动力蛋白激活蛋白复合物的功能，导致纯合基因敲入小鼠早期胚胎致死。正常发育的杂合基因敲入小鼠在10月龄后表现出MND样表型，包括神经肌肉接头处细胞骨架和突触小泡蛋白过度积累、脊髓运动神经元丧失、反应性星形胶质细胞增生增加，与野生型同窝小鼠和年龄匹配的p150（glued）杂合基因敲除小鼠相比，步态缩短。我们的研究结果表明，p150（glued）中的G59S突变消除了p150（glued）的正常功能，并加速了运动神经元退化。
Zotero 插件