Evaluating Protein Quality Control in the Toxicity of TDP43 Fragments Associated with ALS and FTD

评估与 ALS 和 FTD 相关的 TDP43 片段毒性的蛋白质质量控​​制

• 批准号: 10571257
• 负责人: Christopher Scott Brower
• 金额: $ 7.21万
• 依托单位: TEXAS WOMAN'S UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10571257
• 关键词: BCL2 gene; Brain; Cell physiology; Cells; Defect; Disease; Excision; Goals; Hydrophobicity; Mediating; Metabolism; Morphology; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Normal Cell; Parents; Pathway interactions; Persons; Protein Fragment; Proteins; Proteolysis; Quality Control; Reporting; Risk; System; Toxic effect; Training; Triage; frontotemporal lobar dementia-amyotrophic lateral sclerosis; graduate student; insight; novel; prevent; protein TDP-43; protein aggregation; protein degradation

Project Summary People are living longer, which increases their risk of developing neurodegenerative disorders. Such disorders can be characterized by the accumulation and aggregation of specific proteins in the brain. These aggregates often contain protein fragments produced by increases in protein cleavage or defects in protein quality control systems such as regulated protein degradation. Our overall goal is to understand the effects of protein aggregates on normal cell function and to identify cellular pathways that prevent toxicity. Previously we found that the N-termini of fragments associated with neurodegenerative disorders influence their metabolism, tendency to aggregate, and the morphology of their aggregates. We also reported that specific fragments of the TAR DNA Binding Protein 43 (TDP43) could be degraded either by the N-degron pathway or through a Bcl-2-associated athanogene 6 (BAG6)-mediated fashion depending upon the extent of fragment hydrophobicity. The studies proposed in this supplement will evaluate the level of cooperativity between BAG6 and the N- degron pathway to protect cells from intracellular aggregation associated with neurodegeneration. It will also examine whether this cooperatively results in the triaged removal of toxic proteins. This will provide novel insight into how cells are protected from toxicity associated with neurodegeneration. Finally, this sub-project is proposed as a Diversity Supplement to expand Aim 1 of the Parent R15 and to serve as a training vehicle for graduate student Winnie Lokuso.

项目概要 人们的寿命越来越长，这增加了患神经退行性疾病的风险。这样的 疾病的特征是大脑中特定蛋白质的积累和聚集。 这些聚集体通常含有因蛋白质裂解增加而产生的蛋白质片段或 蛋白质质量控​​制系统的缺陷，例如受调控的蛋白质降解。我们的总体目标是 了解蛋白质聚集体对正常细胞功能的影响并确定细胞途径 防止毒性。之前我们发现片段的 N 末端与 神经退行性疾病影响其新陈代谢、聚集倾向和形态 他们的总量。我们还报道了 TAR DNA 结合蛋白 43 的特定片段 (TDP43) 可以通过 N-降解决定子途径或通过 Bcl-2 相关蛋白降解 athanogene 6 (BAG6) 介导的方式取决于片段疏水性的程度。这 本补充中提出的研究将评估 BAG6 和 N-之间的合作水平 降解决定子途径保护细胞免受与神经变性相关的细胞内聚集的影响。它 还将检查这是否能够共同导致有毒蛋白质的分类去除。这将 提供了关于如何保护细胞免受与神经变性相关的毒性的新见解。 最后，该子项目被提议作为多样性补充，以扩展父 R15 的目标 1 并作为研究生 Winnie Lokuso 的培训工具。

项目成果

The N Termini of TAR DNA-Binding Protein 43 (TDP43) C-Terminal Fragments Influence Degradation, Aggregation Propensity, and Morphology.

• DOI: 10.1128/mcb.00243-18
• 发表时间: 2018-10-01
• 期刊: Molecular and cellular biology
• 影响因子: 5.3
• 作者: Kasu YAT;Alemu S;Lamari A;Loew N;Brower CS
• 通讯作者: Brower CS

BAG6 prevents the aggregation of neurodegeneration-associated fragments of TDP43.

• DOI: 10.1016/j.isci.2022.104273
• 发表时间: 2022-05-20
• 期刊: ISCIENCE
• 影响因子: 5.8
• 作者: Kasu, Yasar Arfat T.;Arva, Akshaya;Johnson, Jess;Sajan, Christin;Manzano, Jasmin;Hennes, Andrew;Haynes, Jacy;Brower, Christopher S.
• 通讯作者: Brower, Christopher S.