PMID:20660724

Citation	Lipinski, MM, Zheng, B, Lu, T, Yan, Z, Py, BF, Ng, A, Xavier, RJ, Li, C, Yankner, BA, Scherzer, CR and Yuan, J (2010) Genome-wide analysis reveals mechanisms modulating autophagy in normal brain aging and in Alzheimer's disease. Proc. Natl. Acad. Sci. U.S.A. 107:14164-9
Abstract	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 Abeta 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.
Links	PubMed PMC2922576 Online version:10.1073/pnas.1009485107
Keywords	Aging/genetics; Alzheimer Disease/genetics; Alzheimer Disease/pathology; Amyloid beta-Peptides/metabolism; Autophagy/genetics; Brain/pathology; Brain/physiology; Gene Expression Regulation; Genome-Wide Association Study; Humans; Lysosomes/metabolism; Phosphatidylinositol 3-Kinases/metabolism; Reactive Oxygen Species/metabolism
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
HUMAN:BCL2		GO:0004676: 3-phosphoinositide-dependent protein kinase activity	ECO:0000315:		F		In Fig 1 b and 1 c screen was conducted that showed that the overexpression of Bcl-2 leads to decrease in levels of autophagy and type III P13 kinase. Screen showed that there was an increase in cell viability and decrease in levels of PtdIns3P following knock down of the hit genes in H4 cells expressing Bcl-2 compared to WT controls	complete
HUMAN:COX5A		GO:2000378: negative regulation of reactive oxygen species metabolic process	ECO:0000315:		P		Figure 3a displays how the knock down of Cox5a led to accumulation of reactive oxygen species in H4 cells.	complete CACAO 11839
HUMAN:COX5A		GO:0010507: negative regulation of autophagy	ECO:0000315:		P		Figure 3b displays how the knock down of Cox5a resulted in the induction of autophagy in cells transfected with siRNAs against Cox5a or controls. The autophagy levels were then tested with antibodies against p62m Atg5 (Atg12-Atg5 complex) and LC3.	complete CACAO 11842

References

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