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Enhanced skeletal muscle proteostasis as a determinant of CNS protein quality control and neural function in the aging brain

增强的骨骼肌蛋白质稳态是衰老大脑中中枢神经系统蛋白质质量控制和神经功能的决定因素

基本信息

批准号：
10427660
负责人：
Constanza Javiera Cortes
金额：
$ 5.35万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-15 至 2022-08-31
项目状态：
已结题

项目摘要

PARENT PROJECT ABSTRACT Proteostasis is essential for cell health and viability, and involves complex and highly conserved networks that regulate protein translation, protein folding, and protein degradation. A decline in proteostasis function is one of the features of aging tissues, particularly of the central nervous system (CNS). Indeed, the aging brain is particularly sensitive to proteotoxic stress, as demonstrated by the high number of age-associated neurodegenerative disorders characterized by protein misfolding and aggregation, including Alzheimer’s disease (AD). The regulation of non-cell autonomous proteostasis has recently arisen as a novel mechanism for the modulation of systemic homeostasis in worms and flies, and is postulated to have important organismal effects on metabolism and aging. However, to date, there are no studies addressing the existence and activity of these pathways in mammals, and their potential effects on the aging brain. Transcription Factor E-B (TFEB) is a powerful master transcription factor regulator of proteostasis, integrating autophagy and bioenergetics. We recently derived transgenic mice that moderately overexpress TFEB in skeletal muscle, and discovered that the resulting enhanced skeletal muscle proteostasis function can significantly ameliorate proteotoxicity in the CNS and also improve cognition and memory in aging mice. In this project, we will determine if enhanced skeletal muscle proteostasis is capable of promoting neuroprotection, uncover the mechanistic basis for this effect, develop powerful new models for testing mitophagy/autophagy activity in the aging CNS, and determine if soluble factors secreted by muscle (“myokines”) mediate the beneficial CNS effects in conditional skeletal muscleexpressing TFEB transgenic mice. Identification of pathways regulating cross-talk between skeletal muscle and CNS may yield targets with high therapeutic potential for diseases of the aging CNS.

项目简介蛋白质稳态对于细胞健康和生存力至关重要，并且涉及复杂和高度保守的网络，调节蛋白质翻译、蛋白质折叠和蛋白质降解。蛋白质稳定功能的下降是衰老组织的特征，特别是中枢神经系统（CNS）的特征。事实上，衰老的大脑对蛋白毒性应激特别敏感，如大量与年龄相关的以蛋白质错误折叠和聚集为特征的神经变性疾病，包括阿尔茨海默氏病疾病（AD）。非细胞自主性蛋白质稳态的调节是近年来出现的一种新机制用于调节蠕虫和苍蝇的系统内稳态，并被假定具有重要的生物活性。影响新陈代谢和衰老。然而，到目前为止，还没有研究解决的存在和活动，哺乳动物中这些途径的研究，以及它们对衰老大脑的潜在影响。转录因子E-B（TFEB）是一种功能强大的蛋白质稳态主转录因子调节因子，整合自噬和生物能量学。我们最近获得了转基因小鼠，这些小鼠在哺乳动物中中度过表达TFEB。骨骼肌，并发现由此产生的增强的骨骼肌蛋白质稳态功能可以显著改善CNS中的蛋白毒性，并且还改善衰老小鼠的认知和记忆。在这项目，我们将确定增强骨骼肌蛋白质稳态是否能够促进神经保护，揭示这种效应的机制基础，开发强大的新模型来测试线粒体自噬/自噬活性，并确定是否由肌肉分泌的可溶性因子（“肌因子”）介导衰老的中枢神经系统。在条件性骨骼肌表达TFEB转基因小鼠中有益的CNS作用。鉴定调节骨骼肌和CNS之间的串扰的途径可能产生具有高治疗效果的靶点，可能导致中枢神经系统老化疾病。