Aggregation of mutant Cu/Zn superoxide dismutase proteins in a culture model of ALS
Aggregation of mutant Cu/Zn superoxide dismutase proteins in a culture model of ALS
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DOI：
10.1097/00005072-199705000-00008
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发表时间：
1997-05-01
影响因子：
3.2
通讯作者：
Figlewicz, DA
中科院分区：
文献类型：
--
作者：
Durham, HD;Roy, J;Figlewicz, DA
Cu/Zn-超氧化物歧化酶（SOD-1）基因突变是肌萎缩侧索硬化症（ALS）的一些家族性病例的基础，肌萎缩侧索硬化症是一种以皮质、脑干和脊髓运动神经元丧失为特征的神经退行性疾病。为了研究突变酶的毒性机制，在培养的脊髓运动神经元、背根神经节（DRG）和海马神经元中表达携带在ALS患者中发现的突变（mSOD）的SOD-1 cDNA。运动神经元疾病的许多功能，在人类与FALS和转基因小鼠模型中看到的再现，包括运动神经元的优先易感性的毒性mSOD。在表达mSOD的运动神经元中观察到mSOD蛋白质的异常胞质聚集，但在表达SODwt酶的神经元中从未观察到mSOD蛋白质的异常胞质聚集，并且随后出现凋亡性细胞死亡的证据。在表达mSOD的非脆弱神经元群体（DRG或海马神经元）中未观察到此类聚集体。SOD-1的聚集可能显著促进表达与FALS-1相关的突变的运动神经元的死亡，并且导致聚集的机制可能与这种疾病中运动神经元的特定脆弱性有关。
Mutations in the Cu/Zn-superoxide dismutase (SOD-1) gene underlie some familial cases of amyotrophic lateral sclerosis (FALS), a neurodegenerative disorder characterized by loss of cortical, brainstem, and spinal motor neurons. To investigate the mechanisms responsible for the toxicity of mutant enzyme, SOD-1 cDNAs bearing mutations found in FALS patients (mSOD) were expressed in cultured spinal motor neurons, dorsal root ganglion (DRG) and hippocampal neurons. Many features of motor neuron disease seen in humans with FALS and in transgenic mouse models were reproduced, including preferential susceptibility of motor neurons to toxicity of mSOD. Abnormal cytoplasmic aggregation of mSOD protein was observed in mSOD-expressing motor neurons, but never in neurons expressing SODwt enzyme, and was followed by evidence of apoptotic cell death. Such aggregates were not observed in nonvulnerable neuronal populations expressing mSOD (DRG or hippocampal neurons). Aggregation of SOD-1 may contribute significantly to the death of motor neurons expressing mutations associated with FALS-1 and the mechanisms leading to aggregation may pertain to the specific vulnerability of motor neurons in this disease.