In Vivo Force Measurements Reveal that GSK-3 Regulates Axonal Transport by Altering the Number of Active Motors

Neurons rely on microtubule motor proteins such as kinesin-1 and dynein to transport essential cargos along the axon. Defective transport is connected to neurodegenerative diseases, including Alzheimer's disease. Glycogen Synthase Kinase 3(GSK-3) has been proposed to be a central player in Alzheimer's. We show that GSK-3 is a required negative regulator of both kinesin-1-mediated and dynein-mediated transport of the Amyloid Precursor Protein, a key contributor to Alzheimer's pathology. 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 leading us to propose that this regulation occurs via a mechanism of changing motor-microtubule interactions.