PMID:23585566

Citation	Tang, Z, Bereczki, E, Zhang, H, Wang, S, Li, C, Ji, X, Branca, RM, Lehtiö, J, Guan, Z, Filipcik, P, Xu, S, Winblad, B and Pei, JJ (2013) Mammalian target of rapamycin (mTor) mediates tau protein dyshomeostasis: implication for Alzheimer disease. J. Biol. Chem. 288:15556-70
Abstract	Previous evidence from post-mortem Alzheimer disease (AD) brains and drug (especially rapamycin)-oriented in vitro and in vivo models implicated an aberrant accumulation of the mammalian target of rapamycin (mTor) in tangle-bearing neurons in AD brains and its role in the formation of abnormally hyperphosphorylated tau. Compelling evidence indicated that the sequential molecular events such as the synthesis and phosphorylation of tau can be regulated through p70 S6 kinase, the well characterized immediate downstream target of mTor. In the present study, we further identified that the active form of mTor per se accumulates in tangle-bearing neurons, particularly those at early stages in AD brains. By using mass spectrometry and Western blotting, we identified three phosphoepitopes of tau directly phosphorylated by mTor. We have developed a variety of stable cell lines with genetic modification of mTor activity using SH-SY5Y neuroblastoma cells as background. In these cellular systems, we not only confirmed the tau phosphorylation sites found in vitro but also found that mTor mediates the synthesis and aggregation of tau, resulting in compromised microtubule stability. Changes of mTor activity cause fluctuation of the level of a battery of tau kinases such as protein kinase A, v-Akt murine thymoma viral oncogene homolog-1, glycogen synthase kinase 3β, cyclin-dependent kinase 5, and tau protein phosphatase 2A. These results implicate mTor in promoting an imbalance of tau homeostasis, a condition required for neurons to maintain physiological function.
Links	PubMed PMC3668717 Online version:10.1074/jbc.M112.435123
Keywords	Aged; Aged, 80 and over; Alzheimer Disease/genetics; Alzheimer Disease/metabolism; Brain/metabolism; Brain/physiology; Cell Line, Tumor; Cyclic AMP-Dependent Protein Kinases/genetics; Cyclic AMP-Dependent Protein Kinases/metabolism; Cyclin-Dependent Kinase 5/genetics; Cyclin-Dependent Kinase 5/metabolism; Female; Glycogen Synthase Kinase 3/genetics; Glycogen Synthase Kinase 3/metabolism; Homeostasis; Humans; Male; Middle Aged; Neurons/metabolism; Neurons/pathology; Oncogene Protein v-akt/genetics; Oncogene Protein v-akt/metabolism; Phosphorylation/genetics; Protein Phosphatase 2/genetics; Protein Phosphatase 2/metabolism; TOR Serine-Threonine Kinases/genetics; TOR Serine-Threonine Kinases/metabolism; tau Proteins/genetics; tau Proteins/metabolism
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
HUMAN:MTOR		GO:1902949: positive regulation of tau-protein kinase activity	ECO:0000314:		P		Figure 2 shows mTor directly phosphorylates tau protein	complete CACAO 10618
HUMAN:MTOR		GO:1903032: negative regulation of microtubule plus-end binding	ECO:0000314:		P		Figure 7 shows mTor affects microtubule binding ability	complete CACAO 10619
HUMAN:MTOR		GO:0034109: homotypic cell-cell adhesion	ECO:0000314:		P		Figure 6 shows mTor affects tau aggregation	complete CACAO 10620

References

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