# GSK-3β coordinates axonal microtubule organization through Shot and Tau

## TL;DR

GSK-3β helps organize axonal microtubules through Shot and Tau proteins, and its imbalance can lead to neurodegenerative issues.

## Contribution

Identifies GSK-3β's role in regulating microtubule bundling via Shot and Tau, explaining its link to neurodegeneration.

## Key findings

- GSK-3β regulates microtubule bundling by modulating Shot and Tau proteins.
- Disruption of GSK-3β activity causes microtubule disorganization and axonal swellings.
- GSK-3β's misregulation may explain the failure of global inhibition in clinical trials.

## Abstract

Glycogen Synthase Kinase 3β (GSK-3β) is a crucial regulator of neuronal development and implicated in various neurodegenerative and neurodevelopmental diseases. Yet the cellular mechanisms linking its activity to neuronal development and maintenance remain unclear. We found that GSK-3β maintains axonal microtubule bundles by modulating the dual roles of the microtubule regulators Shot and Tau. Disruption of this balance, either through kinase overactivation or inhibition, leads to pathological unbundling of microtubules, impairing axonal integrity. This work reveals a fundamental role for GSK-3β in organizing the neuronal cytoskeleton, with implications across the diverse cell types and contexts in which GSK-3β functions. Our findings might help explain why broad GSK-3β inhibition has shown limited success in therapeutic settings.

Glycogen Synthase Kinase 3β (GSK-3β) is a key coordinator of neuronal development and maintenance; hyperactive GSK-3β is linked to neurodevelopmental and -degenerative diseases and therefore a promising therapeutic target. In neurons, GSK-3β coordinates the cytoskeleton by phosphorylating microtubule-binding proteins. In this study, we found that tight regulation of GSK-3β kinase activity is required for the maintenance of parallel microtubule bundles in Drosophila and rat axons. Up- or downregulation of GSK-3β led to axons forming pathological swellings in which microtubule bundles disintegrated into disorganized, curled microtubules. We identified the microtubule bundling proteins Shot and Tau as key GSK-3β targets and found that GSK-3β exerted its regulatory effect on microtubule bundling through them. GSK-3β regulates the ability of Shot and Tau to attach to microtubules and/or Eb1. Misregulation of GSK-3β leads to the loss of Eb1–Shot-mediated guidance of polymerizing microtubules into parallel bundles, thus causing disorganization. We propose that microtubule disorganization during both active and inactive states of GSK-3β links its hyperactivity to neurodegeneration and may explain why global GSK-3β inhibition has failed in clinical trials.