Investigation of post-translational modifications in WT SOD1 in sporadic ALS

描述(申请人提供)：肌萎缩侧索硬化症(ALS)，也被称为Lou Gehrig病，是最常见的运动神经元病。肌萎缩侧索硬化症的临床特征是大脑和脊髓运动神经元的变性，最终导致瘫痪和1-5年内死亡。目前，肌萎缩侧索硬化症还没有治愈方法。编码超氧化物歧化酶(SOD1)的基因突变会导致家族性或遗传性肌萎缩侧索硬化(FAL)。ALS占ALS病例的10%，其余90%为散发性(SALS)。虽然SALS和FALS在临床上无法区分，但与SALS相关的致病因素(S)尚不清楚。SOD1基因的150多个突变与FAL有关，但仍不确定SOD1的野生型(WT)形式是否在散发性ALS中起作用。这项建议的总体目标是检验SOD1WT的改变与SALS的致病因素有关的假设。我们设计了我们的实验方法，以解决我们认为必须满足的四个标准，以定义SALS中SOD1WT的因果作用：在SALS标本中检测到修改的SOD1WT(目标1、2和3)；修改的SOD1WT与疾病的致病途径的相关性(目标4和5)；修改的SOD1WT与疾病严重程度之间的适当剂量-反应关系(目标2和5)；以及证明修改的SOD1WT可以在正常宿主或细胞中传播疾病(目标5)。这些实验通过定义疾病机制和确定治疗靶点，有可能显著影响ALS的研究。 公共卫生相关性：肌萎缩侧索硬化症(ALS)，也被称为Lou Gehrig病，是最常见的运动神经元病。虽然10%的ALS病例是家族性或遗传性的，但绝大多数(90%)是散发性的(SAL)。超氧化物歧化酶(SOD1)的突变已被确定为FALS最常见的原因。然而，SALS的起源尚未确定，也不知道野生型(WT)SOD1是否与SALS有关。这项建议的目的是进一步检验WT SOD1的改变与SALS的致病因素有关的假设。

DESCRIPTION (provided by applicant): Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, is the most common motor neuron disease. ALS is clinically characterized by the degeneration of motor neurons in the brain and spinal cord, culminating in paralysis and death within 1-5 years. Presently, there is no cure for ALS. Mutations in the gene encoding superoxide dismutase (SOD1) cause familial, or inheritable, ALS (FALS). FALS constitutes 10% of ALS cases, whereas the remaining 90% are sporadic in nature (SALS). Although SALS and FALS are clinically indistinguishable, the causative factor(s) associated with SALS are unknown. More than 150 mutations in the SOD1 gene have been linked to FALS, and yet it is still undetermined whether the wild-type (WT) form of SOD1 plays a role in sporadic ALS. The overall goal of this proposal is to test the hypothesis that altered modifications of SOD1 WT are implicated as causative factors in SALS. We have designed our experimental approach to address four criteria that in our view must be fulfilled to define a causal role for SOD1 WT in SALS: detection of modified SOD1 WT in SALS specimens (Aims 1, 2 and 3); relevance of modified SOD1 WT to pathogenic pathways in the disease (Aims 4 and 5); an appropriate dose response relationship between modified SOD1 WT and severity of disease (Aims 2 and 5); and demonstration that modified SOD1 WT can propagate the disease in normal hosts or cells (Aim 5). These experiments have the potential to significantly impact ALS research, by defining disease mechanisms and by identifying therapeutic targets. PUBLIC HEALTH RELEVANCE: Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, is the most common motor neuron disease. While 10% of ALS cases are familial or inherited, the vast majority (90%) are sporadic (SALS). Mutations in superoxide dismutase (SOD1) have been identified as the most common cause of FALS. However, the origins of SALS have not been identified, nor is it known if wild-type (WT) SOD1 is involved in SALS. The goal of this proposal is to further test the hypothesis that altered modifications of WT SOD1 are implicated as causative factors in SALS.