Endogenous GSK-3/shaggy regulates bidirectional axonal transport of the amyloid precursor protein

Traffic. 2013 Mar;14(3):295-308. doi: 10.1111/tra.12037. Epub 2013 Jan 20.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amyloid beta-Protein Precursor / metabolism*
  • Animals
  • Axonal Transport*
  • Axons / metabolism
  • Drosophila / genetics
  • Drosophila / metabolism
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism*
  • Dyneins / metabolism
  • Glycogen Synthase Kinase 3 / genetics
  • Glycogen Synthase Kinase 3 / metabolism*
  • Kinesin / metabolism
  • Lipid Metabolism
  • Protein Transport

Substances

  • Amyloid beta-Protein Precursor
  • Drosophila Proteins
  • Sgg protein, Drosophila
  • Glycogen Synthase Kinase 3
  • Dyneins
  • Kinesin