Novel chaperones and neurodegeneration

摘要 蛋白质质量控制对于防止蛋白毒性物质的积累至关重要， 神经退行性疾病因此，了解细胞如何对蛋白毒性物质作出反应是至关重要的， 开发治疗这些疾病的疗法。一类特别容易聚集的蛋白质是 具有均聚氨基酸重复序列的蛋白质，包括多聚谷氨酰胺重复序列。扩展聚谷氨酰胺 重复导致一类九种神经退行性疾病，并了解细胞如何处理长 多聚谷氨酰胺重复将告诉我们如何治疗多聚谷氨酰胺疾病和许多其他疾病， 神经退行性疾病我的团队采取了一种独特的方法来研究细胞如何处理长时间的 多聚谷氨酰胺重复序列。代替在具有蛋白质聚集的生物体中建模多聚谷氨酰胺重复， 我们已经鉴定出细胞黏菌盘基网柄菌对多聚谷氨酰胺具有天然抗性 聚合来网骨藻可能能够完成这一点，因为这种生物体天然编码 近2,500个多聚谷氨酰胺重复序列，其中许多超过了人类的疾病阈值。这一起提高了 问题：网囊藻利用什么新的机制来抑制蛋白质聚集？这里我们 我建议开始使用比较生物学为基础的方法，以确定网骨藻如何响应细胞 驱动蛋白质聚集和神经元死亡的压力源。这些发现可以用于人类细胞 以确定类似的策略是否可以用于增强蛋白质稳态和治疗神经退行性疾病。

Abstract Protein quality control is essential to prevent the accumulation of proteotoxic species that cause neurodegenerative diseases. Therefore, understanding how cells respond to proteotoxic species is essential for developing therapies to treat these diseases. One class of proteins that are especially prone to aggregation are proteins with homopolymeric amino acid repeats, including polyglutamine repeats. Expanded polyglutamine repeats cause a class of nine neurodegenerative diseases and understanding how cells deal with long polyglutamine repeats will inform us about ways to treat the polyglutamine diseases and many other neurodegenerative diseases. My group has taken a unique approach to investigating how cells deal with long polyglutamine repeats. Instead of modeling polyglutamine repeats in organisms that have protein aggregation, we have identified the cellular slime mold Dictyostelium discoideum as being naturally resistant to polyglutamine aggregation. Dictyostelium is likely able to accomplish this due to the fact that this organism naturally encodes nearly 2,500 polyglutamine repeats with many surpassing the disease threshold in humans. Together this raises the question: What novel mechanisms do Dictyostelium utilize to suppress protein aggregation? Here we propose to begin to use a comparative biology-based approach to identify how Dictyostelium respond to cellular stressors that drive protein aggregation and neuronal death. These findings can then be utilized in human cells to determine if similar strategies can be used to enhance proteostasis and treat neurodegenerative diseases.