FAIM Proteostasis in ALS

摘要 这个项目广泛的、长期的目标是阐明异常蛋白质 聚集是在细胞水平上处理的，并确定异常蛋白质之间的关系 聚集/解聚和神经退行性疾病。本提案的具体重点是 研究一种独特的蛋白抑制剂(FAIM)、异常蛋白质聚集和 肌萎缩侧索硬化症。ALS的临床情况很严峻，有运动神经元丧失、进行性瘫痪和死亡， 所有这些都发生在2-5年的短暂病程中。肌萎缩侧索硬化症的病因尚不清楚， 煽动侮辱或前驱疾病已被确认。ALS发病机制的阐明受到以下因素的阻碍 大多数病例为散发性，尽管少数(家族性ALS或FAL)可归因于其中一例的突变 在几个基因中，例如编码SOD1的基因。重要的是，无论是零星的还是家族性的， 肌萎缩侧索硬化症的特点是存在异常的蛋白质聚集物。因为这样的聚集体 已知是有毒的，这种功能失调的蛋白质行为被认为是ALS的关键致病因素。 有人提出，发现一种阻止或逆转蛋白质聚集的试剂可能会 构成了一种改善ALS疾病的手段。 费姆可能就是这样的代理人。虽然最初被克隆为Fas凋亡抑制分子，但我们 最近的研究表明，FAIM具有重要的蛋白抑制活性。面对各种形式的压力， FAIM抑制内源性蛋白质聚集，与此一致，FAIM抵消了细胞活力的丧失 受压力的细胞和动物。此外，FAIM特异性地抑制突变的SOD1和DISAS的聚集- 在无细胞系统中对已建立的突变型SOD1聚合体进行模拟。 我们现在建议进一步研究FAIM与ALS的关系。1)我们将研究FIM的能力 肌萎缩侧索硬化症相关突变型SOD1蛋白对分化的人运动神经元细胞聚集的影响 来自健康对照ipsc，其中faim已被删除或过度表达。2)我们将研究 通过研究疾病的发病、严重程度和转归，以及组织学，FAIM改善ALS的能力 在突变的SOD1ALS疾病模型小鼠中，faim被删除或过表达， 在一般情况下和神经元中都有。这些研究很可能表明，faim可以对抗突变蛋白。 在人类神经元中聚集，并可改善小鼠的ALS疾病。这样的结果将提供证据- 支持FAIM可以使其他家族性和非家族性ALS受益的假设的原则和支持 通过它的蛋白抑制活性。此外，这样的结果将推动对FAIM的重要继续研究 细胞应激状态和其他神经退行性疾病。这项工作可能会暗示一种潜在的 FAIM在改善肌萎缩侧索硬化症和其他可能的神经退行性疾病中的治疗作用。

Summary The broad, long term objectives of this project are to elucidate the mechanisms by which abnormal protein aggregation is handled at the cellular level, and to determine the relationship between abnormal protein aggregation/disaggregation and neurodegenerative disease. The specific focus of the present proposal is to study the inter-relationships among a unique proteostatic agent (FAIM), abnormal protein aggregation, and ALS disease. The clinical picture of ALS is grim, with motor neuron loss, progressive paralysis, and death, all occurring during a brief course of 2-5 years duration. The etiology of ALS remains unknown, and no inciting insult or preceding illness has been identified. Elucidation of ALS pathogenesis is hampered by the sporadic nature of most cases, although a minority (familial ALS or FALS) is attributable to mutation in one of several genes such as the gene encoding SOD1. Importantly, regardless of sporadic or familial origin, all cases of ALS are characterized by the presence of abnormal protein aggregates. Because such aggregates are known to be toxic, this dysfunctional protein behavior is thought to be a key pathogenic element in ALS. It has been suggested that discovery of an agent that prevents or reverses protein aggregation could constitute a means to ameliorate disease in ALS. FAIM may be such an agent. Although originally cloned as Fas Apoptosis Inhibitory Molecule, we recently reported that FAIM manifests important proteostatic activity. In the face of various forms of stress, FAIM inhibits endogenous protein aggregation and, in keeping with this, FAIM counteracts loss of viability in stressed cells and animals. Moreover, FAIM specifically inhibits aggregation of mutant SOD1 and disas- sembles established mutant SOD1 aggregates in cell-free systems. We now propose further study of FAIM in relation to ALS. 1) We will examine the capacity of FAIM to influence aggregation of ALS-associated mutant SOD1 protein in human motor neuron cells differentiated from healthy control iPSC in which FAIM has been deleted or overexpressed. 2) We will examine the capacity of FAIM to improve ALS, by studying disease onset, severity and outcome, plus tissue histologic examination, in mutant SOD1 ALS disease model mice in which FAIM has been deleted or overexpressed, both generally and in neurons. These studies will likely show that FAIM can oppose mutant protein aggregation in human neurons and can improve ALS disease in mice. Such results would provide proof-of- principle and support for the hypothesis that FAIM can benefit other familial, and non-familial, forms of ALS through its proteostatic activity. Further, such results would fuel important continued study of FAIM in cellular stress conditions and in other neurodegenerative diseases. This work could suggest a potential therapeutic role for FAIM in ameliorating ALS and possibly other neurodegenerative diseases.