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

项目摘要 人们的寿命越来越长，这增加了他们患神经退行性疾病的风险。是这样的 疾病的特征可以是大脑中特定蛋白质的积累和聚集。 这些聚集体通常包含蛋白质片段，这些片段是由蛋白质裂解增加或 蛋白质质量控制系统中的缺陷，如受控制的蛋白质降解。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 可以防止有毒物质。之前我们发现片段的N-末端与 神经退行性疾病影响细胞的代谢、聚集倾向和形态。 它们的聚集体。我们还报道了TAR DNA结合蛋白43的特定片段 (TDP43)可通过N-降解子途径或通过与Bcl2相关的途径被降解 基因6(BAG6)介导的方式取决于片段的疏水性程度。这个 本附录中提出的研究将评估BAG6和N- 保护细胞免受与神经变性相关的细胞内聚集的退化子途径。它 还将检查这种合作是否会导致对有毒蛋白质的分类去除。这将是 提供新的洞察力，了解细胞如何受到保护，免受与神经退化相关的毒性。 最后，这一分项目被提议作为多样性补充，以扩大上级R15的目标1 并作为研究生Winnie Lokuso的培训工具。

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.