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（PFN 1）基因内的突变（Wu等人，Nature 2012）。PFN 1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连锁突变诱导PFN 1“错误折叠”（即，适应异常的和潜在致病的构象）。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，并且可能通过正常功能丧失或毒性功能获得机制促成疾病发病机制。我们认为PFN 1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-PFN 1变体的错误折叠构象，然后用小分子靶向这些错误折叠的种类。我们的初步数据还表明，改变肌动蛋白动力学是下游的ALS-PFN 1错误折叠的后果。我们的目的是了解PFN 1介导的ALS的机制，并确定是否改变肌动蛋白动力学与此机制有关。 本文提出的实验将使我们能够实现我们的最终目标，即将ALS领域推向这种毁灭性疾病的有效疗法。

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.