Characterization of KIFAP3, a Modifier of Survival in Sporadic ALS

KIFAP3（散发性 ALS 生存调节因子）的表征

• 批准号: 8056035
• 负责人: JOHN E LANDERS
• 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: 2010-04-15 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8056035
• 关键词: Alleles; Amyotrophic Lateral Sclerosis; Autopsy; Axonal Transport; Binding; Carrier Proteins; Cellular Structures; Complex; Development; Disease; Embryo; FDA approved; Familial Amyotrophic Lateral Sclerosis; Gene Mutation; Genes; Genetic; Homozygote; Human; KRP protein; Kinesin; Longevity; Mediating; Microtubules; Motor Neurons; Mus; Mutation; Neurodegenerative Disorders; Patients; Pharmaceutical Preparations; Play; Proteins; RNA; Reporting; Riluzole; Role; SOD1 gene; Spinal Cord; Tissues; Transgenic Organisms; age related; genetic variant; genome wide association study; molecular pathology; mouse model; mutant; novel strategies; protein aggregate; public health relevance; survival motor neuron gene; therapy development; treatment strategy

DESCRIPTION (provided by applicant): Amyotrophic lateral sclerosis (ALS) is a uniformly lethal, age-dependent neurodegenerative disorder with a typical survival of 2-5 years. With the possible exception of reduced numbers of copies of the SMN gene, or the presence of the SOD1A4V gene mutation, genetic factors that influence survival in ALS have not been described. We recently reported that survival in sporadic ALS is enhanced by genetic variants that reduce expression of KIFAP3, a protein constituent of a kinesin II complex that mediates fast anterograde axonal transport. Homozygotes for the favorable allele have a survival advantage of 14.0 months, a substantial improvement (~42%) that surpasses the magnitude of benefit of the single drug (riluzole) that is FDA approved for ALS in ALS. A recent study documents that KIFAP3 binds misfolded SOD1G93A in ALS mice and is co-localized with the mutant SOD1 protein in aggregates both in the SOD1G93A mouse and in spinal cords of ALS patients bearing mutations in the SOD1 gene. These findings support the view that axonal transport proteins, and KIFAP3 in particular, are determinants of motor neuron viability. This proposal will investigate the mechanisms by which decreased expression of KIFAP3 increases survival in ALS. The Specific Aims of this proposal are to: (1) Analyze the interactions between KIFAP3, SOD1 and other cargoes in human sporadic ALS spinal cords. Hypothesis: Misfolded, wild-type SOD1 binds to KIFAP3 in sporadic ALS but not control spinal cords. (2) Determine the effect of reduced KIFAP3 expression on motor neuron viability and survival in transgenic SOD1G93A mice. Hypothesis: By analogy with survival in human ALS, motor neuron viability and survival in transgenic ALS mice will be enhanced by reduced expression of KIFAP3. (3) Analyze the interactions between KIFAP3, SOD1 and other cargoes in spinal cord from ALS and control mice with normal and reduced levels of KIFAP3. Hypothesis: Decreased expression of KIFAP3 will alter the types and quantities of cargoes transported by KIFAP3. (4) Determine the influence of altered expression levels of KIFAP3 on axonal transport rates in embryonic motor neurons from ALS and control mice. Hypothesis: Altered levels of KIFAP3 expression are not determinants of axonal transport rates. Our proposed studies will elucidate the mechanisms whereby KIFAP3 expression modulates survival in ALS. In the long term, understanding how KIFAP3 influences survival will facilitate the development of therapies to extend the lifespan of ALS patients. PUBLIC HEALTH RELEVANCE: Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, is a uniformly lethal, age-dependent neurodegenerative disorder with a typical survival of 2 to 5 years. Through our efforts, we have identified a gene which can influence the survival advantage of sporadic ALS by 14.0 months, a substantial increment (42%) in this disease. The purpose of this proposal is to understand how this gene influences survival, which will aid in the development of treatment strategies to extend the lifespan of patients afflicted with ALS.

描述（由申请人提供）：肌萎缩侧索硬化症 (ALS) 是一种均致死的、年龄依赖性神经退行性疾病，典型生存期为 2-5 年。除了 SMN 基因拷贝数减少或 SOD1A4V 基因突变的存在之外，影响 ALS 生存的遗传因素尚未被描述。我们最近报道，减少 KIFAP3 表达的基因变异可增强散发性 ALS 的生存率，KIFAP3 是介导快速顺行轴突运输的驱动蛋白 II 复合物的蛋白质成分。有利等位基因的纯合子具有 14.0 个月的生存优势，显着改善 (~42%)，超过了 FDA 批准用于治疗 ALS 的单一药物（利鲁唑）的获益程度。最近的一项研究表明，KIFAP3 与 ALS 小鼠中错误折叠的 SOD1G93A 结合，并与 SOD1G93A 小鼠和携带 SOD1 基因突变的 ALS 患者脊髓中的突变 SOD1 蛋白共定位。这些发现支持这样的观点：轴突转运蛋白，特别是 KIFAP3，是运动神经元活力的决定因素。该提案将研究 KIFAP3 表达减少提高 ALS 患者生存率的机制。该提案的具体目标是： (1) 分析人类散发性 ALS 脊髓中 KIFAP3、SOD1 和其他货物之间的相互作用。假设：错误折叠的野生型 SOD1 在散发性 ALS 中与 KIFAP3 结合，但不控制脊髓。 (2) 确定 KIFAP3 表达减少对转基因 SOD1G93A 小鼠运动神经元活力和存活的影响。假设：与人类 ALS 的存活率类似，转基因 ALS 小鼠的运动神经元活力和存活率将通过减少 KIFAP3 的表达而增强。 (3) 分析 ALS 小鼠和 KIFAP3 水平正常和降低的对照小鼠脊髓中 KIFAP3、SOD1 和其他货物之间的相互作用。假设：KIFAP3 表达的减少将改变 KIFAP3 运输的货物的类型和数量。 (4) 确定 KIFAP3 表达水平改变对 ALS 和对照小鼠胚胎运动神经元轴突转运速率的影响。假设：KIFAP3 表达水平的改变并不是轴突转运速率的决定因素。我们提出的研究将阐明 KIFAP3 表达调节 ALS 患者生存的机制。从长远来看，了解 KIFAP3 如何影响生存将有助于开发延长 ALS 患者寿命的疗法。 公众健康相关性：肌萎缩侧索硬化症 (ALS)，也称为卢伽雷氏病，是一种均致死的、年龄依赖性神经退行性疾病，典型生存期为 2 至 5 年。通过我们的努力，我们发现了一种基因，可以使散发性 ALS 的生存优势延长 14.0 个月，使这种疾病的生存优势显着增加 (42%)。该提案的目的是了解该基因如何影响生存，这将有助于制定延长 ALS 患者寿命的治疗策略。