Alzheimer's presenilin 1 mutations impair kinesin-based axonal transport.
Several lines of evidence indicate that alterations in axonal transport play a critical role in Alzheimer's disease (AD) neuropathology, but the molecular mechanisms that control this process are not understood fully. Recent work indicates that presenilin 1 (PS1) interacts with glycogen synthase kinase 3beta (GSK3beta). In vivo, GSK3beta phosphorylates kinesin light chains (KLC) and causes the release of kinesin-I from membrane-bound organelles (MBOs), leading to a reduction in kinesin-I driven motility (Morfini et al., 2002b). To characterize a potential role for PS1 in the regulation of kinesin-based axonal transport, we used PS1-/- and PS1 knock-inM146V (KIM146V) mice and cultured cells. We show that relative levels of GSK3beta activity were increased in cells either in the presence of mutant PS1 or in the absence of PS1 (PS1-/-). Concomitant with increased GSK3beta activity, relative levels of KLC phosphorylation were increased, and the amount of kinesin-I bound to MBOs was reduced. Consistent with a deficit in kinesin-I-mediated fast axonal transport, densities of synaptophysin- and syntaxin-I-containing vesicles and mitochondria were reduced in neuritic processes of KIM146V hippocampal neurons. Similarly, we found reduced levels of PS1, amyloid precursor protein, and synaptophysin in sciatic nerves of KIM146V mice. Thus PS1 appears to modulate GSK3beta activity and the release of kinesin-I from MBOs at sites of vesicle delivery and membrane insertion. These findings suggest that mutations in PS1 may compromise neuronal function by affecting GSK-3 activity and kinesin-I-based motility.
Pigino
Gustavo
G
Department of Neuroscience, University of Connecticut Health Center, Farmington, Connecticut 06030, USA.
Morfini
Gerardo
G
Pelsman
Alejandra
A
Mattson
Mark P
MP
Brady
Scott T
ST
Busciglio
Jorge
J
D000544:Alzheimer Disease / Q000235:genetics*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D001370:Axonal Transport / Q000235:genetics*; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000235:genetics; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D020439:Growth Cones / Q000378:metabolism; D006801:Humans; D016547:Kinesins / Q000378:metabolism*; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism; D009154:Mutation; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D010766:Phosphorylation; D011233:Precipitin Tests; D053764:Presenilin-1; D016708:Synaptophysin / Q000378:metabolism; D014162:Transfection
D016564:Amyloid beta-Protein Precursor; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1; D016708:Synaptophysin; D038362:Glycogen Synthase Kinase 3; D016547:Kinesins