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

Glycogen Synthase Kinase 3{beta} (GSK-3{beta}) is a key coordinator of neuronal development and maintenance; hyperactive GSK-3{beta} is linked to neurodevelopmental and -degenerative diseases and therefore a promising therapeutic target. In neurons, GSK-3{beta} coordinates the cytoskeleton by phosphorylating microtubule-binding proteins. In this study, we found that tight regulation of GSK-3{beta} kinase activity is required for the maintenance of parallel microtubule bundles in Drosophila and rat axons. Up- or down-regulation of GSK-3{beta} led to axons forming pathological swellings in which microtubule bundles disintegrated into disorganised, curled microtubules. We identified the microtubule bundling proteins Shot and Tau as key GSK-3{beta} targets and found that GSK-3{beta} exerted its regulatory effect on microtubule bundling through them. GSK-3{beta} regulates the ability of Shot and Tau to attach to microtubules and/or the plus-end protein Eb1. Mis-regulation of GSK-3{beta} leads to the loss of Eb1-Shot-mediated guidance of polymerising microtubules into parallel bundles, thus causing disorganisation. We propose microtubule disorganisation as a new explanation for how GSK-3{beta} hyperactivity leads to neurodegeneration and why global inhibition of GSK-3{beta} has not been successful in clinical trials for neuronal disorders.