FAIM Proteostasis in ALS

ALS 中的 FAIM 蛋白质稳态

• 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
• 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

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 聚集在细胞水平上处理，并确定异常蛋白之间的关系 聚集/分类和神经退行性疾病。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病。 ALS的临床情况很严峻，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年的短期内。 ALS的病因仍然未知，没有 已经确定了煽动侮辱或先前的疾病。 ALS发病机理的阐明受到阻碍 大多数情况的零星性质，尽管少数族裔（家族性ALS或伪造）归因于一种突变 几种基因，例如编码SOD1的基因。重要的是，无论零星或家族性如何 ALS病例的特征是存在异常的蛋白质聚集体。因为这样的聚合 已知有毒，这种功能失调的蛋白质行为被认为是ALS中的关键致病元素。 有人提出，发现阻止或逆转蛋白质聚集的药物可能 构成一种改善ALS疾病的手段。 Faim可能是这样的经纪人。尽管最初以FAS凋亡抑制性分子的克隆，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，并且与此相符，Faim抵消了在 压力细胞和动物。此外，FAIM专门抑制突变SOD1和灾难的聚集 SEMBLES在无细胞系统中建立了突变的SOD1聚集体。 现在，我们提出了与ALS有关的FAIM的进一步研究。 1）我们将研究Faim的能力 影响人类运动神经元细胞中与ALS相关突变体SOD1蛋白的聚集 从健康对照IPSC中，FAIM已被删除或过表达。 2）我们将检查 通过研究疾病发作，严重程度和结果，以及组织学，FAIM改善ALS的能力 检查，在突变的SOD1 ALS疾病模型中，FAIM已被删除或过表达， 一般都在神经元中。这些研究可能表明FAIM可以反对突变蛋白 人神经元的聚集，可以改善小鼠的ALS疾病。这样的结果将提供证明 原则和对FAIM可以使其他家庭和非家庭形式的假设的支持和支持 通过其蛋白抑制活性。此外，这样的结果将推动对FAIM的重要研究 细胞应激条件和其他神经退行性疾病。这项工作可能暗示潜力 FAIM在改善ALS和可能其他神经退行性疾病的治疗作用。