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

描述（由申请人提供）：肌萎缩性侧索硬化症（ALS），又称Lou Gehrig病，是最常见的运动神经元疾病。ALS的临床特征是脑和脊髓运动神经元的退化，最终在1-5年内瘫痪和死亡。目前，还没有治愈ALS的方法。编码超氧化物歧化酶（SOD1）的基因突变导致家族性或遗传性ALS （FALS）。FALS占ALS病例的10%，而其余90%为散发性（SALS）。尽管SALS和FALS在临床上难以区分，但与SALS相关的致病因素尚不清楚。超过150个SOD1基因突变与ALS有关，但是野生型SOD1是否在散发性ALS中起作用仍不确定。本提案的总体目标是验证SOD1 WT的改变修饰与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SOD1 WT在SALS中的因果作用：在SALS标本中检测到修饰的SOD1 WT（目标1、2和3）；修饰的SOD1 WT与疾病致病途径的相关性（目的4和5）；改良SOD1 WT与疾病严重程度之间存在适当的剂量反应关系（目标2和5）；并证明修饰的SOD1 WT可以在正常宿主或细胞中传播疾病（目标5）。通过确定疾病机制和确定治疗靶点，这些实验有可能对ALS研究产生重大影响。

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.