Bilsland Lynsey G, Nirmalananthan Niranjanan, Yip Jing, Greensmith Linda, Duchen Michael R
Sobell Department of Movement Disorders and Motor Neuroscience, Institute of Neurology, Queen Square, London, UK.
J Neurochem. 2008 Dec;107(5):1271-83. doi: 10.1111/j.1471-4159.2008.05699.x. Epub 2008 Oct 25.
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 Ca(2+) were elevated in SOD1(G93A) motoneurons, changes in mitochondrial function did not correlate with Ca(2+). 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.
肌萎缩侧索硬化症（ALS）是一种致命的神经退行性疾病，其特征是运动神经元退化，导致瘫痪并最终死亡。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元细胞在疾病发病机制中起着重要作用。尽管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%。我们在原代星形胶质细胞与运动神经元共培养模型中，研究了星形胶质细胞中SOD1（G93A）的表达对运动神经元线粒体稳态的影响。星形胶质细胞中SOD1（G93A）的表达诱导了SOD1（G93A）和野生型运动神经元线粒体功能的变化。在存在SOD1（G93A）星形胶质细胞的情况下，野生型和SOD1（G93A）运动神经元的线粒体氧化还原状态均降低，线粒体膜电位下降。虽然SOD1（G93A）运动神经元的线粒体内钙水平[Ca(2+)]m升高，但线粒体功能的变化与[Ca(2+)]m无关。因此，星形胶质细胞中SOD1（G93A）的表达即使在胚胎运动神经元中也直接改变线粒体功能，而与基因型无关。周围星形胶质细胞诱导的这些早期线粒体功能缺陷可能会增加运动神经元对ALS发病机制中其他神经毒性机制的易感性。
