Steady-state increase of cAMP-response element binding protein, Rac, and PAK signaling in presenilin-deficient neurons.
Mutations in the genes encoding presenilins (PS1 and PS2) account for the majority of cases of early-onset Alzheimer's disease. PS1 and PS2 form the catalytic center of gamma-secretase, an enzyme responsible for intramembraneous proteolysis of several type I transmembrane proteins. Many gamma-secretase substrates are coupled to intracellular signaling events such as cAMP-response element binding protein and Rac1/p21-activated kinase pathways, which are associated with synaptic function. Here, we have examined the activation of these pathways in neurons lacking PS1 expression or gamma-secretase activity. We found evidence for heightened steady-state activation of cAMP-response element binding protein, Rac1, and p21-activated kinase signaling in PS-deficient neurons. Our study highlights the importance of PS-dependent proteolytic cleavage of gamma-secretase substrates in regulating neuronal signal transduction.
Barnes
Natalie Y
NY
Department of Neurobiology, University of Chicago, Chicago, Illinois 60637, USA.
Shi
Jun
J
Yajima
Hiroshi
H
Thinakaran
Gopal
G
Parent
Angèle T
AT
D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D009479:Neuropeptides / Q000378:metabolism*; D053764:Presenilin-1 / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D054462:p21-Activated Kinases / Q000378:metabolism*; D020744:rac GTP-Binding Proteins / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein
C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D009479:Neuropeptides; D053764:Presenilin-1; C484602:Rac1 protein, mouse; D054462:p21-Activated Kinases; D053829:Amyloid Precursor Protein Secretases; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein