Expression of mutant SOD1G93A in astrocytes induces functional deficits in motoneuron mitochondria
Expression of mutant SOD1G93A in astrocytes induces functional deficits in motoneuron mitochondria
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DOI：
10.1111/j.1471-4159.2008.05699.x
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发表时间：
2008-12-01
影响因子：
4.7
通讯作者：
Duchen, Michael R.
中科院分区：
文献类型：
--
作者：
Bilsland, Lynsey G.;Nirmalananthan, Niranjanan;Duchen, Michael R.
肌萎缩侧索硬化症(ALS)是一种以运动神经元变性为特征的致死性神经退行性疾病，可导致瘫痪和最终死亡。ALS被认为是一种运动神经元特异性疾病，但越来越多的证据表明，非神经细胞在疾病的发病机制中发挥了重要作用。虽然ALS的确切病因尚不清楚，但已知超氧化物歧化酶(SOD1)基因突变约占家族性ALS的20%。在原代星形胶质细胞-运动神经元共培养模型中，我们检测了星形胶质细胞SOD1(G93A)的表达对运动神经元线粒体稳态的影响。SOD1(G93A)在星形胶质细胞中的表达引起SOD1(G93A)和野生型运动神经元线粒体功能的改变。在SOD1(G93A)星形胶质细胞存在下，野生型和SOD1(G93A)运动神经元的线粒体氧化还原状态均明显降低，线粒体膜电位降低。虽然SOD1(G93A)运动神经元的线粒体内钙水平升高，但线粒体功能的改变与[Ca2+]m无关。因此，SOD1(G93A)在星形胶质细胞中的表达直接改变线粒体功能，甚至在胚胎运动神经元中也是如此，而不受基因型的影响。这些由周围星形胶质细胞引起的线粒体功能早期缺陷可能会增加运动神经元对参与ALS发病机制的其他神经毒性机制的易感性。
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by motoneuron degeneration resulting in paralysis and eventual death. ALS is regarded as a motoneuron-specific disorder but increasing evidence indicates non-neuronal cells play a significant role in disease pathogenesis. Although the precise aetiology of ALS remains unclear, mutations in the superoxide dismutase (SOD1) gene are known to account for approximately 20% of familial ALS. We examined the influence of SOD1(G93A) expression in astrocytes on mitochondrial homeostasis in motoneurons in a primary astrocyte : motoneuron co-culture model. SOD1(G93A) expression in astrocytes induced changes in mitochondrial function of both SOD1(G93A) and wild-type motoneurons. In the presence of SOD1(G93A) astrocytes, mitochondrial redox state of both wild-type and SOD1(G93A) motoneurons was more reduced and mitochondrial membrane potential decreased. While intra-mitochondrial calcium levels [Ca2+] m were elevated in SOD1(G93A) motoneurons, changes in mitochondrial function did not correlate with [Ca2+] m. Thus, expression of SOD1(G93A) in astrocytes directly alters mitochondrial function even in embryonic motoneurons, irrespective of genotype. These early deficits in mitochondrial function induced by surrounding astrocytes may increase the vulnerability of motoneurons to other neurotoxic mechanisms involved in ALS pathogenesis.