Mitochondria in Amyotrophic Lateral Sclerosis

肌萎缩侧索硬化症（Amyotrophic lateral sclerosis，ALS）是一种破坏性的神经退行性疾病，其影响脊髓和大脑皮层的运动神经元，导致进行性瘫痪和过早死亡。 虽然大多数病例是散发性的，并且由于未知的原因，但约5-10%是家族性的（FALS），其中约25%与Cu/Zn超氧化物歧化酶（SOD 1）基因突变有关。这些突变是ALS的第一个确定的原因，他们的发现允许开发该疾病的转基因小鼠模型。 在散发性和ALS患者的运动神经元中以及在小鼠模型中已经报道了异常的线粒体和受损的线粒体呼吸链功能。越来越多的证据表明，受损的线粒体能量产生和线粒体中氧化自由基形成的增加以及线粒体DNA（mtDNA）的损伤可能与ALS中运动神经元的死亡有因果关系。事实上，一些研究已经假设运动神经元变性与mtDNA异常有关。 为了明确线粒体改变在ALS发病机制中的作用，我们提出了以下研究。 1)分析ALS转基因小鼠在不同疾病阶段和表达突变型人SOD 1的培养细胞中脑和脊髓中的线粒体功能。用脑和脊髓的突触体构建胞质杂交体，分析ALS转基因小鼠的mtDNA。2)研究转基因动物和表达野生型和突变型h SOD 1的培养神经母细胞瘤细胞中定位于线粒体的SOD 1的结构特性和功能效应。3)分析ALS患者个体运动神经元的呼吸链功能和mtDNA。 我们认为，更好地理解ALS中线粒体功能障碍的分子基础将有助于我们了解运动神经元丢失的机制，在某些情况下甚至可能确定疾病的主要原因，对治疗策略产生潜在影响。

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease, which affects motor neurons of the spinal cord and cerebral cortex, leading to progressive paralysis and premature death. While the majority of the cases are sporadic and due to unknown causes, about 5-10% are familial (FALS), and of those approximately 25% are associated with mutations in the gene for Cu/Zn superoxide dismutase (SOD1). These mutations are the first identified cause of ALS, and their finding has allowed the development of a transgenic mouse model of the disease. Abnormal mitochondria and impaired mitochondrial respiratory chain function have been reported in motor neurons of patients with sporadic and ALS, as well as in the mouse models. A growing body of evidence suggests that impaired mitochondrial energy production and increased oxidative radical formation in the mitochondria and damage to the mitochondrial DNA (mtDNA) could be causally involved in motor neuron death in ALS. Indeed, several studies have postulated the involvement of mtDNA abnormalities in motor neuron degeneration. To define the role of mitochondrial alterations in the pathogenesis of ALS, we propose the following studies. 1) Analyze mitochondrial functions in brain and spinal cord in ALS transgenic mice at various stages of disease and in cultured cells expressing mutant human SOD1. Analyze the mtDNA from ALS transgenic mice in cybrids constructed with synaptosomes from brain and spinal cords. 2) Study the structural properties and the functional effects of SOD1 localized to mitochondria in transgenic animals and in cultured neuroblastoma cells expressing wild type and mutated h SOD1. 3) Analyze respiratory chain functions and mtDNA in individual motor neurons from ALS patients. We think that a better comprehension of the molecular basis of mitochondrial dysfunction in ALS will help us to understand the mechanisms responsible for the motor neuron loss and, in some cases may even identify the primary cause of the disease, with a potential impact on therapeutic strategies.