FAIM Proteostasis in ALS

ALS 中的 FAIM 蛋白质稳态

基本信息

批准号：
10527540
负责人：
THOMAS L ROTHSTEIN
金额：
$ 41.53万
依托单位：
WESTERN MICHIGAN UNIV SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10527540
关键词：
ALS patients Acute Address Affect Amyotrophic Lateral Sclerosis Animal Disease Models Animals Apoptosis Awareness B-Lymphocytes Behavior Brain Cell Differentiation process Cell-Free System Cells Cellular Stress Cessation of life Clinical Cognition Deterioration Disease Disease model Elements Etiology Foundations Future Genes Genetic Genetic study Histologic Human Knowledge Life Link Mediating Mediator of activation protein Minority Modeling Motor Motor Neurons Mus Muscle Weakness Mutation Names Nature Neurodegenerative Disorders Neurons Onset of illness Outcome Paralysed Pathogenesis Pathogenicity Pathology Patients Pattern Physiology Play Primary Lateral Sclerosis Progressive Disease Proteins Pulmonary Valve Insufficiency Regulation Reporting Resistance Role Severities Spinal Cord Stress Stress-Induced Protein Testing Therapeutic Tissues Toxic effect Ursidae Family Work acronyms familial amyotrophic lateral sclerosis improved induced pluripotent stem cell mouse model mutant neuron loss novel overexpression prevent protein TDP-43 protein aggregation proteostasis receptor superoxide dismutase 1

项目摘要

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.

概括该项目的广泛、长期目标是阐明异常蛋白质的机制在细胞水平上处理聚集，并确定异常蛋白质之间的关系聚集/分解和神经退行性疾病。本提案的具体重点是研究独特的蛋白质抑制剂 (FAIM)、异常蛋白质聚集和 ALS 疾病。 ALS 的临床表现十分严峻，伴有运动神经元丧失、进行性瘫痪，甚至死亡，所有这些都发生在2-5年的短暂过程中。 ALS 的病因尚不清楚，目前尚无定论已确定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呈散发性，尽管少数病例（家族性 ALS 或 FALS）可归因于其中一个病例的突变一些基因，例如编码 SOD1 的基因。重要的是，无论是散发性还是家族性起源，所有 ALS 病例的特征是存在异常蛋白质聚集体。因为这样的聚集体已知具有毒性，这种功能失调的蛋白质行为被认为是 ALS 的关键致病因素。有人建议发现一种防止或逆转蛋白质聚集的药物可以构成改善 ALS 疾病的一种手段。 FAIM可能就是这样的一个代理人。虽然最初被克隆为 Fas 凋亡抑制分子，但我们最近报道 FAIM 表现出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，与此相一致，FAIM 可以抵消细胞活力的丧失应激细胞和动物。此外，FAIM 特异性抑制突变型 SOD1 的聚集，并抑制类似物在无细胞系统中建立了突变型 SOD1 聚集体。我们现在建议进一步研究 FAIM 与 ALS 的关系。 1) 我们将检查 FAIM 的能力影响分化的人运动神经元细胞中 ALS 相关突变 SOD1 蛋白的聚集来自健康对照 iPSC，其中 FAIM 已被删除或过度表达。 2）我们将检查 FAIM 通过研究疾病的发作、严重程度和结果以及组织组织学来改善 ALS 的能力在突变型 SOD1 ALS 疾病模型小鼠中进行检查，其中 FAIM 已被删除或过表达，一般情况下和神经元中。这些研究可能表明 FAIM 可以对抗突变蛋白人类神经元中的聚集，可以改善小鼠的 ALS 疾病。这样的结果将提供证明- FAIM 可以使其他家族性和非家族性 ALS 形式受益的假设的原理和支持通过其蛋白抑制活性。此外，这些结果将推动 FAIM 的重要持续研究细胞应激状况和其他神经退行性疾病。这项工作可能表明一个潜在的 FAIM 在改善 ALS 和可能的其他神经退行性疾病中的治疗作用。