Palmer Jennifer E, Wilson Niall, Son Sung Min, Obrocki Pawel, Wrobel Lidia, Rob Matea, Takla Michael, Korolchuk Viktor I, Rubinsztein David C
Cambridge Institute for Medical Research, Department of Medical Genetics, University of Cambridge, Cambridge Biomedical Campus, The Keith Peters Building, Hills Road, Cambridge CB2 0XY, UK; UK Dementia Research Institute, University of Cambridge, Cambridge Biomedical Campus, The Keith Peters Building, Hills Road, Cambridge CB2 0XY, UK.
Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE4 5PL, UK.
Neuron. 2025 Jan 8;113(1):29-48. doi: 10.1016/j.neuron.2024.09.015. Epub 2024 Oct 14.
Autophagy is a conserved mechanism that degrades damaged or superfluous cellular contents and enables nutrient recycling under starvation conditions. Many neurodegeneration-associated proteins are autophagy substrates, and autophagy upregulation ameliorates disease in many animal models of neurodegeneration by enhancing the clearance of toxic proteins, proinflammatory molecules, and dysfunctional organelles. Autophagy inhibition also induces neuronal and glial senescence, a phenomenon that occurs with increasing age in non-diseased brains as well as in response to neurodegeneration-associated stresses. However, aging and many neurodegeneration-associated proteins and mutations impair autophagy. This creates a potentially detrimental feedback loop whereby the accumulation of these disease-associated proteins impairs their autophagic clearance, facilitating their further accumulation and aggregation. Thus, understanding how autophagy interacts with aging, senescence, and neurodegenerative diseases in a temporal, cellular, and genetic context is important for the future clinical application of autophagy-modulating therapies in aging and neurodegeneration.
自噬是一种保守的机制，可降解受损或多余的细胞内容物，并在饥饿条件下实现营养物质的循环利用。许多与神经退行性变相关的蛋白质都是自噬底物，在许多神经退行性变动物模型中，自噬上调通过增强有毒蛋白质、促炎分子和功能失调细胞器的清除来改善疾病。自噬抑制也会诱导神经元和神经胶质细胞衰老，这种现象在未患病的大脑中随着年龄增长而出现，也会在对神经退行性变相关应激的反应中出现。然而，衰老以及许多与神经退行性变相关的蛋白质和突变会损害自噬。这就形成了一个潜在的有害反馈循环，即这些与疾病相关的蛋白质的积累会损害它们的自噬清除，促进它们进一步积累和聚集。因此，了解自噬如何在时间、细胞和基因背景下与衰老、衰老和神经退行性疾病相互作用，对于自噬调节疗法在衰老和神经退行性变中的未来临床应用至关重要。
