Genome-wide analysis reveals mechanisms modulating autophagy in normal brain aging and in Alzheimer's disease
Genome-wide analysis reveals mechanisms modulating autophagy in normal brain aging and in Alzheimer's disease
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DOI：
10.1073/pnas.1009485107
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发表时间：
2010-08-10
影响因子：
11.1
通讯作者：
Yuan, Junying
中科院分区：
文献类型：
--
作者：
Lipinski, Marta M.;Zheng, Bin;Yuan, Junying
自噬的失调是一种细胞分解代谢机制，对错误折叠的蛋白质的降解至关重要，已被认为与多种神经退行性疾病有关。然而，导致自噬功能障碍的机制仍不清楚。基于全基因组筛选的结果，我们发现，活性氧物种(ROS)是III型PI3激酶激活的上游常见介质，这是启动自噬的关键。此外，ROS在诱导III型PI3激酶和自噬反应中发挥重要作用，淀粉样β蛋白是阿尔茨海默病(AD)的主要致病介质。然而，溶酶体的阻断也是由Aβ引起的，这与ROS无关。此外，我们还证明，在人脑正常衰老过程中，自噬在转录水平上被下调。引人注目的是，与正常衰老相反，我们观察到AD患者大脑中自噬的转录上调，表明可能存在自噬的代偿性调节。有趣的是，我们发现AD药物和AD候选药物对自噬有抑制作用，这增加了减少溶酶体系统的输入可能有助于减少AD细胞应激的可能性。最后，我们提供了一个候选药物靶点列表，可用于安全地调节自噬水平，而不会导致细胞死亡。
Dysregulation of autophagy, a cellular catabolic mechanism essential for degradation of misfolded proteins, has been implicated in multiple neurodegenerative diseases. However, the mechanisms that lead to the autophagy dysfunction are still not clear. Based on the results of a genome-wide screen, we show that reactive oxygen species (ROS) serve as common mediators upstream of the activation of the type III PI3 kinase, which is critical for the initiation of autophagy. Furthermore, ROS play an essential function in the induction of the type III PI3 kinase and autophagy in response to amyloid beta peptide, the main pathogenic mediator of Alzheimer's disease (AD). However, lysosomal blockage also caused by A beta is independent of ROS. In addition, we demonstrate that autophagy is transcriptionally down-regulated during normal aging in the human brain. Strikingly, in contrast to normal aging, we observe transcriptional up-regulation of autophagy in the brains of AD patients, suggesting that there might be a compensatory regulation of autophagy. Interestingly, we show that an AD drug and an AD drug candidate have inhibitory effects on autophagy, raising the possibility that decreasing input into the lysosomal system may help to reduce cellular stress in AD. Finally, we provide a list of candidate drug targets that can be used to safely modulate levels of autophagy without causing cell death.