The cellular protein quality control machinery is important for preventing protein misfolding and aggregation. Declining protein homeostasis (proteostasis) is believed to play a crucial role in age-related neurodegenerative disorders. However, how neuronal proteostasis capacity changes in different diseases is not yet sufficiently understood, and progress in this area has been hampered by the lack of tools to monitor proteostasis in mammalian models. Here, we have developed reporter mice for in vivo analysis of neuronal proteostasis. The mice express EGFP-fused firefly luciferase (Fluc-EGFP), a conformationally unstable protein that requires chaperones for proper folding, and that reacts to proteotoxic stress by formation of intracellular Fluc-EGFP foci and by reduced luciferase activity. Using these mice, we provide evidence for proteostasis decline in the aging brain. Moreover, we find a marked reaction of the Fluc-EGFP sensor in a mouse model of tauopathy, but not in mouse models of Huntington’s disease. Mechanistic investigations in primary neuronal cultures demonstrate that different types of protein aggregates have distinct effects on the cellular protein quality control. Thus, Fluc-EGFP reporter mice enable new insights into proteostasis alterations in different diseases.

中文翻译：

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Fluc-EGFP 报告小鼠揭示了衰老和疾病中神经元蛋白质稳态的不同改变

细胞蛋白质质量控​​制机制对于防止蛋白质错误折叠和聚集很重要。下降的蛋白质稳态（proteostasis）被认为在与年龄相关的神经退行性疾病中起着至关重要的作用。然而，尚未充分了解神经元蛋白质稳态能力如何在不同疾病中发生变化，并且由于缺乏监测哺乳动物模型中蛋白质稳态的工具，该领域的进展受到阻碍。在这里，我们开发了用于体内的报告小鼠神经元蛋白质稳态分析。小鼠表达 EGFP 融合的萤火虫荧光素酶 (Fluc-EGFP)，这是一种构象不稳定的蛋白质，需要分子伴侣才能正确折叠，并且通过形成细胞内 Fluc-EGFP 病灶和降低的荧光素酶活性对蛋白毒性应激作出反应。使用这些小鼠，我们提供了衰老大脑中蛋白质稳态下降的证据。此外，我们发现 Fluc-EGFP 传感器在 tau 蛋白病小鼠模型中有明显反应，但在亨廷顿病小鼠模型中没有。原代神经元培养的机理研究表明，不同类型的蛋白质聚集体对细胞蛋白质质量控​​制有不同的影响。因此，Fluc-EGFP 报告小鼠使人们能够对不同疾病中的蛋白质稳态改变有了新的认识。