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

散发性 ALS 中 WT SOD1 翻译后修饰的研究

• 批准号: 8248066
• 负责人: Daryl Angela Bosco
• 金额: $ 35.26万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-15 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8248066
• 关键词: Address; Amyloid beta-Protein; Amyotrophic Lateral Sclerosis; Antibodies; Axonal Transport; Biological Assay; Brain; Cells; Cerebrospinal Fluid; Cessation of life; Cultured Cells; Detection; Disease; Dose; Familial Amyotrophic Lateral Sclerosis; Genes; Goals; Human; In Vitro; Individual; Inherited; Investigation; Link; Mass Spectrum Analysis; Measures; Modeling; Modification; Molecular Conformation; Motor Neuron Disease; Mus; Mutation; Nature; Neurodegenerative Disorders; Paralysed; Parkinson Disease; Pathogenesis; Pathway interactions; Patients; Phenotype; Play; Post-Translational Protein Processing; Property; Proteins; Recombinants; Research; Role; SOD1 gene; Serum; Severities; Severity of illness; Specimen; Spinal Cord; Squid; Superoxide Dismutase; Testing; Tissues; Toxic effect; axoplasm; design; disorder control; familial Alzheimer disease; in vivo; motor neuron degeneration; mutant; neurotoxic; protein TDP-43; public health relevance; research study; response; synuclein; therapeutic target

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.

描述（由申请人提供）：肌萎缩性侧索硬化症（ALS），也被称为Lou Gehrig病，是最常见的运动神经元疾病。ALS的临床特征是大脑和脊髓中运动神经元的变性，在1-5年内达到瘫痪和死亡的高潮。目前，没有治愈ALS的方法。编码超氧化物歧化酶（SOD 1）的基因突变会导致家族性或遗传性ALS（FALS）。ALS占ALS病例的10%，而其余90%是散发性的（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。SOD 1基因中有超过150个突变与ALS有关，但野生型（WT）形式的SOD 1是否在散发性ALS中起作用仍不确定。该提案的总体目标是检验SOD 1 WT的改变修饰被认为是SALS的致病因素的假设。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SOD 1 WT在SALS中的因果作用：检测SALS标本中修饰的SOD 1 WT（目的1、2和3）;修饰的SOD 1 WT与疾病中致病途径的相关性（目的4和5）;改良SOD 1 WT与疾病严重程度之间的适当剂量反应关系（目的2和5）;以及证明修饰的SOD 1 WT可以在正常宿主或细胞中传播疾病（目的5）。这些实验有可能通过定义疾病机制和确定治疗靶点来显著影响ALS研究。 公共卫生相关性：肌萎缩性侧索硬化症（ALS），也被称为Lou Gehrig病，是最常见的运动神经元疾病。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（SALS）。超氧化物歧化酶（SOD 1）的突变已被确定为最常见的原因。然而，SALS的起源尚未确定，也不知道野生型（WT）SOD 1是否参与SALS。该提议的目的是进一步检验WT SOD 1的改变修饰是SALS的致病因素这一假设。