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。等 疾病的特征在于脑中特定蛋白质的积累和聚集。 这些聚集体通常含有通过增加蛋白质裂解或 蛋白质质量控制系统的缺陷，如受调节的蛋白质降解。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，并识别细胞途径 防止中毒以前我们发现，与 神经退行性疾病影响它们的代谢、聚集倾向和形态 他们的聚集。我们还报道了TAR DNA结合蛋白43的特定片段， （TDP 43）可以通过N-降解决定子途径或通过Bcl-2相关的 产氧基因6（BAG 6）介导的方式取决于片段疏水性的程度。的 本附录中提出的研究将评估BAG 6和N- 降解决定子途径以保护细胞免于与神经变性相关的细胞内聚集。它 还将研究这是否会导致有毒蛋白质的分类去除。这将 提供了新的见解如何保护细胞免受与神经变性相关的毒性。 最后，建议将该子项目作为多样性补充，以扩展父R15的目标1 并作为研究生温妮洛库索的训练车。

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.