FAIM Proteostasis in ALS

总结 这个项目的广泛的，长期的目标是阐明异常蛋白质 在细胞水平上处理聚集，并确定异常蛋白质 聚集/解聚和神经变性疾病。本提案的具体重点是 研究独特的蛋白质抑制剂（FAIM），异常蛋白质聚集， ALS病肌萎缩侧索硬化症的临床表现是严峻的，伴随着运动神经元丧失、进行性瘫痪和死亡， 所有这些都发生在2-5年的短暂过程中。ALS的病因仍然未知， 已查明煽动侮辱或先前患病。ALS发病机制的阐明受到以下因素的阻碍： 大多数病例的散发性质，尽管少数（家族性ALS或FALS）可归因于一种基因突变。 例如编码SOD 1的基因。重要的是，无论是散发性的还是家族性的， ALS病例的特征在于存在异常蛋白质聚集体。因为这样的聚合物 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。 有人认为，发现一种防止或逆转蛋白质聚集的药物， 构成改善ALS疾病的手段。 FAIM可能就是这样一个代理人。尽管最初克隆为Fas凋亡抑制分子， 最近报道FAIM显示重要的蛋白质抑制活性。面对各种形式的压力， FAIM抑制内源性蛋白质聚集，并且与此一致，FAIM抵消了细胞存活力的丧失。 应激细胞和动物。此外，FAIM特异性地抑制突变SOD 1和disas-1的聚集。 sembles在无细胞系统中建立了突变体SOD 1聚集体。 我们现在建议进一步研究FAIM与ALS的关系。1)我们将审查FAIM的能力， ALS相关突变SOD 1蛋白对分化后人运动神经元细胞聚集影响 来自FAIM已经缺失或过表达的健康对照iPSC。2)我们会研究 FAIM改善ALS的能力，通过研究疾病发作、严重程度和结局，加上组织组织学 检查，在FAIM已缺失或过表达的突变型SOD 1 ALS疾病模型小鼠中， 无论是一般的还是在神经元中。这些研究将可能表明FAIM可以对抗突变蛋白 聚集在人类神经元中，并可以改善小鼠的ALS疾病。这些结果将提供证据- 原则和支持的假设，FAIM可以受益于其他家族，和非家族，ALS的形式 通过它的蛋白抑制活性。此外，这些结果将推动重要的FAIM继续研究， 细胞应激条件和其他神经退行性疾病。这项工作可能意味着 FAIM在改善ALS和可能的其他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.