Characterization of KIFAP3, a Modifier of Survival in Sporadic ALS

KIFAP3（散发性 ALS 生存调节因子）的表征

基本信息

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
项目类别：
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

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

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项目摘要

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）：肌萎缩性侧索硬化症（ALS）是一种均匀致命的，年龄依赖性的神经退行性疾病，典型的生存率为2-5岁。除了减少SMN基因拷贝数量或SOD1A4V基因突变的存在外，尚未描述影响ALS存活的遗传因素。我们最近报道说，散发性ALS的生存是通过遗传变异的增强的，遗传变异降低了KIFAP3的表达，KIFAP3的表达是KIFAP3的表达，这是介导快速的同类轴突转运的驱动蛋白II复合物的蛋白质成分。有利的等位基因的纯合子具有14.0个月的生存优势，其大幅改善（〜42％）超过了获得ALS中ALS的FDA批准的单一药物（riluzole）的益处。最近的一项研究记录了KIFAP3在ALS小鼠中结合了错误折叠的SOD1G93A，并与SOD1G93A小鼠的聚集体中的突变体SOD1蛋白共定位，并在SOD1基因中具有突变的ALS患者的脊髓中的骨骼。这些发现支持了轴突转运蛋白尤其是KIFAP3是运动神经元生存能力的决定因素。该建议将研究KIFAP3表达降低的机制，可在ALS中增加生存率。该建议的具体目的是：（1）分析人类零星ALS脊髓中KIFAP3，SOD1与其他货物之间的相互作用。假设：错误折叠的野生型SOD1与零星ALS中的KIFAP3结合，但不能控制脊髓。（2）确定降低KIFAP3表达对转基因SOD1G93A小鼠的运动神经元生存力和存活的影响。假设：通过类似于人类ALS的存活，运动神经元的生存力和转基因ALS小鼠的存活率将通过降低KIFAP3的表达来增强。（3）分析来自ALS和对照小鼠的KIFAP3，SOD1与其他kifap3水平降低的脊髓中的其他货物之间的相互作用。假设：KIFAP3表达的降低将改变KIFAP3运输的货物的类型和数量。（4）确定KIFAP3表达水平改变的影响对ALS和对照小鼠的胚胎运动神经元中轴突转运率的影响。假设：KIFAP3表达水平的改变不是轴突运输速率的决定因素。我们提出的研究将阐明KIFAP3表达调节ALS生存的机制。从长远来看，了解KIFAP3如何影响生存将有助于延长ALS患者寿命的疗法的发展。公共卫生相关性：肌萎缩性侧索硬化症（ALS），也称为Lou Gehrig病，是一种统一致命的，年龄依赖性的神经退行性疾病，典型的生存率为2至5年。通过我们的努力，我们确定了一个基因，该基因可以影响零星ALS的生存优势，到14.0个月，在该疾病中有实质性的增长（42％）。该提案的目的是了解该基因如何影响生存，这将有助于制定治疗策略，以延长患有ALS的患者的寿命。