title: Endogenous GSK-3/shaggy regulates bidirectional axonal transport of the amyloid precursor protein.
abstract: Neurons rely on microtubule (MT) motor proteins such as kinesin-1 and dynein to transport essential cargos between the cell body and axon terminus. Defective axonal transport causes abnormal axonal cargo accumulations and is connected to neurodegenerative diseases, including Alzheimer's disease (AD). Glycogen synthase kinase 3 (GSK-3) has been proposed to be a central player in AD and to regulate axonal transport by the MT motor protein kinesin-1. Using genetic, biochemical and biophysical approaches in Drosophila melanogaster, we find that endogenous GSK-3 is a required negative regulator of both kinesin-1-mediated and dynein-mediated axonal transport of the amyloid precursor protein (APP), a key contributor to AD pathology. GSK-3 also regulates transport of an unrelated cargo, embryonic lipid droplets. By measuring the forces motors generate in vivo, we find that GSK-3 regulates transport by altering the activity of kinesin-1 motors but not their binding to the cargo. These findings reveal a new relationship between GSK-3 and APP, and demonstrate that endogenous GSK-3 is an essential in vivo regulator of bidirectional APP transport in axons and lipid droplets in embryos. Furthermore, they point to a new regulatory mechanism in which GSK-3 controls the number of active motors that are moving a cargo.
authors.affiliation: Department of Cellular and Molecular Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Carole
authors.initials: C
authors.lastname: Weaver
authors.forename: Christina
authors.initials: C
authors.lastname: Leidel
authors.forename: Lukasz
authors.initials: L
authors.lastname: Szpankowski
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Farley
authors.forename: George T
authors.initials: GT
authors.lastname: Shubeita
authors.forename: Lawrence S B
authors.initials: LS
authors.lastname: Goldstein
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D001370:Axonal Transport; D001369:Axons / Q000378:metabolism; D004330:Drosophila / Q000235:genetics / Q000378:metabolism; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004398:Dyneins / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D016547:Kinesins / Q000378:metabolism; D050356:Lipid Metabolism; D021381:Protein Transport
chemical_list: D016564:Amyloid beta-Protein Precursor; D029721:Drosophila Proteins; C080335:Sgg protein, Drosophila; D038362:Glycogen Synthase Kinase 3; D004398:Dyneins; D016547:Kinesins