The Convergence of Titin and Elongator in Amyotrophic Lateral Sclerosis

肌萎缩侧索硬化症中肌联蛋白和伸长剂的融合

• 批准号: 10580407
• 负责人: LYNN D GEORGE
• 金额: $ 38.55万
• 依托单位: MONTANA STATE UNIVERSITY -BILLINGS
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10580407
• 关键词: ALS patients; Amyotrophic Lateral Sclerosis; Biogenesis; Bioinformatics; Catalytic Domain; Cell Aging; Cell Nucleolus; Cell Nucleus; Codon Nucleotides; Communication; Complex; Confocal Microscopy; Cytoplasm; Data; Data Analyses; Development; Diagnosis; Disease; Exhibits; Familial Dysautonomia; Functional disorder; Genes; Genetic Polymorphism; Goals; Homeostasis; Human; Immunohistochemistry; Inherited; Knockout Mice; Mediating; Mission; Modeling; Molecular; Motor; Motor Neuron Disease; Motor Neurons; Mus; Muscle Cells; Muscle function; Mutation; Nature; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Organelles; Pathogenesis; Pathogenicity; Pathologic; Pathway interactions; Patients; Peripheral Nervous System; Phenotype; Play; Production; Proteins; Proteome; Proteomics; Regulation; Research; Ribosomes; Role; Sarcomeres; Severity of illness; Site; Skeletal Muscle; Stress; Testing; Transcript; Translations; cell type; cholinergic; cholinergic neuron; conditional knockout; connectin; effective therapy; experience; genome wide association study; insight; motor neuron degeneration; nervous system disorder; neuron loss; novel; therapeutically effective; tool; transcriptome sequencing; undergraduate student

Project Summary Amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease that ravages motor neurons and the voluntary muscles they innervate, is the most common motor neuron disease. Nucleolar stress was recently identified as an underlying pathogenic mechanism in ALS, common to both familial and sporadic forms, that triggers the degeneration of motor neurons. This proposal describes the discovery that titin, the largest protein in the human proteome, is present in the nucleolus of motor neurons and seeks to demonstrate that its function in this organelle and its regulation by the Elongator complex converge on the nucleolus as a nexus of disease pathogenesis in ALS. The proposal includes three Aims. In the first aim, titin’s presence in neurons will be fully characterized including identification of the specific central and peripheral nervous system cell types that exhibit nucleolar. The second aim will test the hypothesis that titin, encoded by TTN, is required for motor neuron homeostasis and that titin dysfunction represents a novel underlying pathogenic mechanism in ALS. The use of a conditional knockout mouse where TTN is selectively ablated in motor neurons will serve as a powerful approach for investigating this hypothesis. The third aim seeks to understand why mutations in the Elongator complex are associated with ALS and posits that Elongator may actually regulate the production of titin as a common underlying mechanism of disease. Mice in which the Elongator protein 1 (Elp1) is selectively ablated in motor neurons exhibit severely compromised motor function, demonstrating that the loss of Elp1 is sufficient to arrive at an ALS phenotype. These mice again provide a powerful tool for investigating Elongator targets whose misregulation contribute to ALS. Accomplishment of the described specific aims will significantly advance our understanding of the underlying molecular and cellular pathways that go awry to precipitate the onset and progression of ALS and will identify new targets for the development of effective therapeutics to treat the disease.

项目摘要 肌萎缩侧索硬化症（ALS）是一种致命的神经退行性疾病， 运动神经元及其支配的随意肌损伤是最常见的运动神经元疾病。 核仁应激最近被确定为ALS的潜在致病机制， 常见于家族性和散发性形式，引发运动神经元的退化。 这项提议描述了这样一个发现，即肌联蛋白是人类蛋白质组中最大的蛋白质， 存在于运动神经元的核仁中，并试图证明其在这一过程中的功能。 细胞器和它的调节由延长复合体汇聚在核仁作为一个连接的 ALS的发病机制该提案包括三个目标。在第一个目标中， 神经元中的存在将被充分表征，包括识别特定的中枢和 表现出核仁的周围神经系统细胞类型。第二个目标将考验 假设由TTN编码的肌联蛋白是运动神经元稳态所需的， 功能障碍代表了ALS中新的潜在致病机制。的使用 其中TTN在运动神经元中被选择性消融的条件性敲除小鼠将用作运动神经元的治疗剂。 这是一个强有力的方法来研究这个假设。第三个目标是要弄清楚为什么 Elongator复合体中的突变与ALS相关，并假定Elongator可能 实际上调节肌联蛋白的产生，这是疾病的一种常见潜在机制。小鼠 在运动神经元中选择性消融的延伸蛋白1（Elongator protein 1，Elp1）表现出严重的 受损的运动功能，表明Elp1的缺失足以导致ALS 表型这些小鼠再次提供了一个强大的工具，用于研究延长器的目标， 失调会导致ALS实现上述具体目标将 显著推进我们对潜在的分子和细胞途径的理解， 走错了，以沉淀ALS的发病和进展，并将确定新的目标， 开发有效的治疗方法来治疗这种疾病。

项目成果

Loss of Elp1 perturbs histone H2A.Z and the Notch signaling pathway.

• DOI: 10.1242/bio.058979
• 发表时间: 2021-09-15
• 期刊: Biology open
• 影响因子: 2.4
• 作者: Cameron B;Lehrmann E;Chih T;Walters J;Buksch R;Snyder S;Goffena J;Lefcort F;Becker KG;George L
• 通讯作者: George L

Titin is a nucleolar protein in neurons.

肌联蛋白是神经元中的一种核仁蛋白。

• DOI: 10.21203/rs.3.rs-4000799/v1
• 发表时间: 2024
• 期刊: Research square
• 作者: Cameron,BreAnna;Torres-Hernandez,Lauryn;Montague,VirginiaLynne;Lewis,KarenA;Smith,Heidi;Fox,James;Guo,Xueshui;Kalb,RobertG;George,Lynn
• 通讯作者: George,Lynn

Elongator and codon bias regulate protein levels in mammalian peripheral neurons.

• DOI: 10.1038/s41467-018-03221-z
• 发表时间: 2018-03-01
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Goffena J;Lefcort F;Zhang Y;Lehrmann E;Chaverra M;Felig J;Walters J;Buksch R;Becker KG;George L
• 通讯作者: George L

Elongator regulates the melanocortin satiety pathway.

• DOI: 10.1016/j.bbrc.2022.04.128
• 发表时间: 2022-07-12
• 期刊: BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
• 影响因子: 3.1
• 作者: Walters, Joseph;Walters, Cody;Cameron, BreAnna;George, Lynn
• 通讯作者: George, Lynn

Erratum to: Animal and cellular models of familial dysautonomia.

勘误表：家族性自主神经功能障碍的动物和细胞模型。

• DOI: 10.1007/s10286-017-0453-3
• 发表时间: 2017
• 期刊: Clinical autonomic research : official journal of the Clinical Autonomic Research Society
• 作者: Lefcort,Frances;Mergy,Marc;Ohlen,SarahB;Ueki,Yumi;George,Lynn
• 通讯作者: George,Lynn