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

摘要 蛋白质平衡对细胞的健康和活力是必不可少的，它涉及复杂和高度保守的 调节蛋白质翻译、蛋白质折叠和蛋白质降解的网络。……的下降 蛋白平衡功能是衰老组织的特征之一，尤其是中枢神经系统 (CNS)。事实上，老化的大脑对蛋白毒性压力特别敏感，这一点从 大量与年龄相关的神经退行性疾病，其特征是蛋白质错误折叠和 聚集，包括阿尔茨海默病(AD)。非细胞自主蛋白平衡的调控 最近出现了一种新的机制，用于调节蠕虫和 苍蝇，并被认为对新陈代谢和衰老有重要的有机影响。然而，为了 到目前为止，还没有关于哺乳动物中这些通路的存在和活动的研究，并且 它们对老化的大脑的潜在影响。 转录因子E-B(TFEB)是蛋白质平衡的主要转录因子调节因子， 整合了自噬和生物能量学。我们最近获得了转基因小鼠，这些小鼠- 在骨骼肌中表达TFEB，并发现由此产生的增强的骨骼肌 蛋白平衡功能可以显著改善中枢神经系统的蛋白毒性，并改善认知功能 以及衰老小鼠的记忆力。在这个项目中，我们将确定增强的骨骼肌蛋白平衡 能够促进神经保护，揭示这种作用的机制基础，发展强大 测试老化中枢神经系统中有丝分裂吞噬/自噬活性的新模型，并确定可溶性因子 肌肉分泌的肌动蛋白在条件性骨骼肌中介导有益的中枢神经系统效应-- 表达TFEB转基因小鼠。骨骼间串扰调节通路的识别 肌肉和中枢神经系统可能产生对衰老的中枢神经系统疾病具有高治疗潜力的靶点。

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 over- express 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 muscle- expressing 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.