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

描述(申请人提供)：最近，我们发现Profilin-1(PFN1)基因突变可导致家族性或遗传性肌萎缩侧索硬化症(Wu等人，《自然》2012)。PFN1编码一种肌动蛋白结合蛋白，它在重要的神经元过程中调节肌动蛋白的动态，如生长、运动和信号传递。我们的初步数据表明，与肌萎缩侧索硬化症相关的突变导致PFN1“错误折叠”(即适应异常的和潜在的致病构象)。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显著特征，可能通过失去正常或获得毒性功能机制而导致疾病的发病机制。我们假设，在最终导致ALS的致病级联中，PFN1的错误构象具有上游功能。因此，这项建议的重点是表征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。我们的初步数据也表明，肌动蛋白动力学的改变是ALS-PFN1错误折叠的下游结果。我们的目的是了解PFN1介导的肌萎缩侧索硬化症的机制，并确定肌动蛋白动力学变化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领域朝着这种毁灭性疾病的有效治疗迈进。

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.