Mis-regulation of GSK-3β causes axonal microtubule curling through Shot and Tau

Abstract

AbstractGlycogen Synthase Kinase 3β (GSK-3β) is a key coordinator of neuronal development and maintenance; overactive GSK-3β is linked to neurodevelopmental and -degenerative diseases making it a highly promising therapeutic target. One of GSK-3β’s key roles in neurons is to coordinate the cytoskeleton by directly phosphorylating microtubule binding proteins. However, how GSK-3β orchestrates the activities of a range of microtubule regulators, to jointly maintain microtubule bundles is not well understood. We study the function of GSK-3β using fly primary neurons, a uniquely tractable system which has allowed us to unravel the function of >50 cytoskeletal regulators in the past. Here we report a novel function of GSK-3β. We find that kinase activity needs to be tightly regulated to maintain parallel microtubule bundles in axons. Functional up-as well as down-regulation of GSK-3β leads to axons forming pathological swellings where microtubule bundles disintegrate into criss-crossed curling microtubules. Mechanistically, we have identified Shot and Tau as key GSK-3β targets, providing a means to change microtubule behaviours in a time and location-specific manner. By modifying the ability of Shot and Tau to attach to microtubules and Eb1, both hyperactivity as well as inhibition of GSK-3β leads to the loss of Eb1-Shot-mediated guidance of polymerising microtubules into parallel bundles, thus causing disorganisation. Our findings provide new explanations how overactivity of GSK-3β could lead to neurodegeneration in neurodegenerative diseases and why global inhibition of GSK-3β has not been successful in clinical trials for those disorders.