Genome-wide analysis reveals mechanisms modulating autophagy in normal brain aging and in Alzheimer's disease.
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.
Lipinski
Marta M
MM
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
Zheng
Bin
B
Lu
Tao
T
Yan
Zhenyu
Z
Py
Bénédicte F
BF
Ng
Aylwin
A
Xavier
Ramnik J
RJ
Li
Cheng
C
Yankner
Bruce A
BA
Scherzer
Clemens R
CR
Yuan
Junying
J
D000375:Aging / Q000235:genetics*; D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D001343:Autophagy / Q000235:genetics*; D001921:Brain / Q000473:pathology / Q000502:physiology*; D005786:Gene Expression Regulation; D055106:Genome-Wide Association Study; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism
D016229:Amyloid beta-Peptides; D017382:Reactive Oxygen Species; D019869:Phosphatidylinositol 3-Kinases