Misfolded ALS-linked Profilin-1: a novel therapeutic target

错误折叠的 ALS 连接的 Profilin-1：一个新的治疗靶点

• 批准号: 9084682
• 负责人: Daryl Angela Bosco
• 金额: $ 36.48万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-15 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9084682
• 关键词: Actin-Binding Protein; Actins; Amyotrophic Lateral Sclerosis; Binding; Binding Proteins; Biochemical; Biological Assay; Cell Line; Cells; Computer Simulation; Data; Disease; Event; Fluorescence Microscopy; Genes; Goals; Growth; Growth Cones; Health; Human; In Vitro; Induced Mutation; Inherited; Label; Lead; Life; Light; Link; Mediating; Metabolic; Microfilaments; Modeling; Molecular Conformation; Motor Neurons; Mutation; Nature; Neurites; Neurodegenerative Disorders; Neurons; Pathogenesis; Play; Process; Proteins; Proteomics; Publications; Recombinants; Reporting; Role; Seminal; Signal Transduction; Structure; System; Testing; Time; Variant; X-Ray Crystallography; base; biophysical techniques; cell motility; effective therapy; in vivo; induced pluripotent stem cell; insight; loss of function; mutant; new therapeutic target; profilin 1; protein misfolding; research study; small molecule; tool

DESCRIPTION (provided by applicant): Recently, we identified mutations within the profilin-1 (PFN1) gene that cause familial, or inherited, ALS (Wu, et al., Nature 2012). PFN1 encodes an actin-binding protein that modulates actin dynamics in the context of important neuronal processes such as growth, motility and signaling. Our preliminary data demonstrate that ALS-linked mutations induce PFN1 to "misfold" (i.e., adapt an aberrant and potentially pathogenic conformation). Protein misfolding is a hallmark feature of ALS and other neurodegenerative disorders, and may contribute to disease pathogenesis through either loss-of-normal or gain-of toxic function mechanisms. We posit that a misfolded conformation of PFN1 functions upstream in the pathogenic cascade that culminates in ALS. Therefore, a focus of this proposal is to characterize the misfolded conformation of ALS-PFN1 variants and to then target these misfolded species with small molecules. Our preliminary data also suggests that altered actin dynamics is a downstream consequence of ALS-PFN1 misfolding. We aim to understand the mechanism of PFN1-mediated ALS, and to determine whether altered actin dynamics is relevant to this mechanism. The experiments proposed herein will allow us to achieve our ultimate goal, which is to move the ALS field forward towards effective therapies for this devastating disease.

描述（由申请人提供）：最近，我们确定了引起家族性或遗传的profilin-1（pfn1）基因中的突变（Wu等人，自然，2012年）。 PFN1编码一种肌动蛋白结合蛋白，该蛋白在重要的神经元过程（例如生长，运动和信号传导）的背景下调节肌动蛋白动力学。 我们的初步数据表明，ALS连接的突变会诱导PFN1“错误折叠”（即适应异常且潜在的致病构象）。蛋白质错误折叠是ALS和其他神经退行性疾病的标志性特征，并且可能通过损失正常或有毒功能机制来促进疾病发病机理。我们认为，在ALS中达到高潮的致病级联反应中，PFN1函数的错误折叠构象。因此，该提案的重点是表征ALS-PFN1变体的错误折叠构象，然后用小分子靶向这些错误折叠的物种。我们的初步数据还表明，改变的肌动蛋白动力学是ALS-PFN1错误折叠的下游结果。我们旨在了解PFN1介导的ALS的机制，并确定肌动蛋白动力学是否与该机制相关。 本文提出的实验将使我们能够实现我们的最终目标，也就是说，将ALS领域推向这种毁灭性疾病的有效疗法。