title: A novel CDK5-dependent pathway for regulating GSK3 activity and kinesin-driven motility in neurons.
abstract: Neuronal transmission of information requires polarized distribution of membrane proteins within axonal compartments. Membrane proteins are synthesized and packaged in membrane-bounded organelles (MBOs) in neuronal cell bodies and later transported to axons by microtubule-dependent motor proteins. Molecular mechanisms underlying targeted delivery of MBOs to discrete axonal subdomains (i.e. nodes of Ranvier or presynaptic terminals) are poorly understood, but regulatory pathways for microtubule motors may be an essential step. In this work, pharmacological, biochemical and in vivo experiments define a novel regulatory pathway for kinesin-driven motility in axons. This pathway involves enzymatic activities of cyclin-dependent kinase 5 (CDK5), protein phosphatase 1 (PP1) and glycogen synthase kinase-3 (GSK3). Inhibition of CDK5 activity in axons leads to activation of GSK3 by PP1, phosphorylation of kinesin light chains by GSK3 and detachment of kinesin from transported cargoes. We propose that regulating the activity and localization of components in this pathway allows nerve cells to target organelle delivery to specific subcellular compartments. Implications of these findings for pathogenesis of neurodegenerative diseases such as Alzheimer's disease are discussed.
authors.affiliation: Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, IL 60612, USA.
authors.forename: Gerardo
authors.initials: G
authors.lastname: Morfini
authors.forename: Györgyi
authors.initials: G
authors.lastname: Szebenyi
authors.forename: Hannah
authors.initials: H
authors.lastname: Brown
authors.forename: Harish C
authors.initials: HC
authors.lastname: Pant
authors.forename: Gustavo
authors.initials: G
authors.lastname: Pigino
authors.forename: Scott
authors.initials: S
authors.lastname: DeBoer
authors.forename: Uwe
authors.initials: U
authors.lastname: Beffert
authors.forename: Scott T
authors.initials: ST
authors.lastname: Brady
mesh_terms: D000818:Animals; D001370:Axonal Transport / Q000502:physiology*; D002465:Cell Movement / Q000187:drug effects*; D002478:Cells, Cultured; D051360:Cyclin-Dependent Kinase 5; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism*; D049832:Decapodiformes; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D020439:Growth Cones / Q000378:metabolism; D015151:Immunoblotting; D007150:Immunohistochemistry; D016547:Kinesins / Q000378:metabolism*; D007700:Kinetics; D007701:Kinetin; D008954:Models, Biological; D016501:Neurites / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D019319:Okadaic Acid / Q000494:pharmacology; D010766:Phosphorylation; D011485:Protein Binding; D011687:Purines / Q000494:pharmacology; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D013379:Substrate Specificity
chemical_list: D004791:Enzyme Inhibitors; D011687:Purines; D011994:Recombinant Proteins; D019319:Okadaic Acid; C090046:olomoucine; D051360:Cyclin-Dependent Kinase 5; C495907:Cdk5 protein, rat; D018844:Cyclin-Dependent Kinases; D038362:Glycogen Synthase Kinase 3; D016547:Kinesins; D007701:Kinetin