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，我们发现了 profilin-1 (PFN1) 基因内的突变会导致家族性或遗传性 ALS（Wu 等人，Nature 2012）。 PFN1 编码一种肌动蛋白结合蛋白，可在生长、运动和信号传导等重要神经元过程中调节肌动蛋白动力学。 我们的初步数据表明，ALS 相关突变会诱导 PFN1“错误折叠”（即适应异常且潜在致病的构象）。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，可能通过正常丧失或毒性功能增强机制导致疾病发病机制。我们推测 PFN1 的错误折叠构象在致病级联反应的上游发挥作用，最终导致 ALS。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，肌动蛋白动力学的改变是 ALS-PFN1 错误折叠的下游结果。我们的目标是了解 PFN1 介导的 ALS 机制，并确定改变的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，即推动 ALS 领域朝着有效治疗这种毁灭性疾病的方向发展。