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

描述（由申请人提供）：最近，我们发现了导致家族性或遗传性ALS的profilin-1 （PFN1）基因突变（Wu, et al., Nature 2012）。PFN1编码一种肌动蛋白结合蛋白，在重要的神经元过程（如生长、运动和信号传导）中调节肌动蛋白动力学。我们的初步数据表明，als相关突变诱导PFN1“错误折叠”（即适应异常和潜在的致病构象）。蛋白质错误折叠是肌萎缩侧索硬化症和其他神经退行性疾病的一个标志性特征，可能通过丧失正常功能或获得毒性功能机制导致疾病发病。我们假设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，本文的一个重点是表征ALS-PFN1变异的错误折叠构象，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错误折叠的下游后果。我们的目的是了解pfn1介导的ALS的机制，并确定肌动蛋白动力学的改变是否与这一机制有关。这里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。

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.