Mechanism of FUS Mutations in the Pathogenesis of ALS

描述（由申请人提供）： ALS是一种由中枢神经系统运动神经元选择性变性引起的致命性疾病。ALS患者患有严重的肌肉萎缩/无力，最终死于呼吸衰竭。最近的遗传数据表明，FUS基因突变可以在超过5%的家族性和散发性ALS患者中发现。其他遗传原因，如FUS突变的鉴定，强烈表明迫切需要开发新的模型系统来了解这些突变，并确定这些毁灭性疾病的治疗靶点。FUS突变的ALS患者的一个重要病理特征是运动神经元变性前存在异常蛋白质聚集体。然而，目前尚不清楚异常的蛋白质聚集体是否直接导致运动神经元的变性。基于FUS作为RNA结合蛋白的功能，我们假设FUS突变干扰正常的RNA/蛋白质合成，最终导致细胞死亡和运动神经元突触的退化。为了进一步研究FUS突变的机制，我们建议建立细胞和小鼠模型来表征FUS突变蛋白在RNA转运和合成中的作用。我们的目标是建立细胞和转基因小鼠模型，以确定突变FUS蛋白如何导致神经元细胞死亡和维持神经肌肉接头。在支持这一观点，我们的数据表明，脊髓运动神经元在转基因小鼠表达突变FUS蛋白质显示严重破坏RNA和蛋白质合成机制。这些令人兴奋的结果让我们相信，我们提出的实验在治疗理念奖的两年资助期内是高度可实现的。它们进一步提供了强有力的支持，这些模型将作为开发高通量药物筛选的新平台，以鉴定可以阻断运动神经元中的细胞死亡并恢复神经肌肉接头处的神经支配的治疗靶点。

DESCRIPTION (provided by applicant): ALS is a fatal disease caused by the selective degeneration of motor neurons in the central nervous system. Patients with ALS suffer from severe muscle wasting/weakness and eventually die from respiratory failure. Recent genetic data have shown that mutations in the FUS gene can be identified in more than 5% of patients with familial and sporadic ALS. The identification of additional genetic causes, such as FUS mutations, strongly indicate the urgent needs to develop new model systems to understand these mutations and to identify therapeutic targets for these devastating diseases. One important pathological feature in ALS patients with FUS mutations is the presence of abnormal protein aggregates in motor neurons prior to their degeneration. However, it is unclear if abnormal protein aggregates directly contribute to the degeneration of the motor neurons. Based on the function of FUS as a RNA binding protein, we hypothesize that mutation in FUS interferes with normal RNA/protein synthesis, which ultimately leads to cell death and the degeneration of motor neuron synapses. To further investigate the mechanisms of FUS mutations, we propose to establish cellular and mouse models to characterize the effects of FUS mutant proteins in RNA transport and synthesis. Our goal is to establish both cellular and transgenic mouse models to determine how mutant FUS proteins lead to neuronal cell death and the maintenance of the neuromuscular junction. In support of this view, our data indicate that spinal motor neurons in transgenic mice expressing mutant FUS proteins show severe disruption in RNA and protein synthesis machinery. These exciting results give us the confidence that our proposed experiments are highly achievable within the two years funding period of the Therapeutic Idea Award. They further provide strong supports that these models will serve as novel platforms for the development of high throughput drug screening to identify therapeutic targets that can block cell death in motor neurons and restore innervation at the neuromuscular junction.