Genome-wide analysis reveals mechanisms modulating autophagy in normal brain aging and in Alzheimer's disease

By Marta M. Lipinski, Bin Zheng, Tao Lu, Zhenyu Yan, B. Py, Aylwin Ng, Ramnik J. Xavier, Cheng Li, B. Yankner, C. Scherzer and 1 more. Proceedings of the National Academy of Sciences of the United States of America, 2010

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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 β peptide, the main pathogenic mediator of Alzheimer's disease (AD). However, lysosomal blockage also caused by Aβ 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.

Subfields: Epidemiology, Neurology, Physiology

View Paper: https://www.semanticscholar.org/paper/1295774725054da3098f38bbeec241a253ed8f98

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Citations in the corpus

Autophagy and aging. (2011, background): “lated) (Lipinski et al., 2010), insulin resistance and metabolic syndrome (in which Sirtuin1 is downregulated) (de Kreutzenberg et al.”
Autophagy and apoptosis dysfunction in neurodegenerative disorders. (2014, neutral): “up-regulated (Lipinski et al., 2010)”
Neuronal Cell Death. (2018, neutral): “However, others reported that, in contrast to normal aging, there is a transcriptional upregulation of autophagic genes in the brains of AD patients, but whether this results in increased autophagic flux remains to be determined (411).”