Presenilin influences glycogen synthase kinase-3 [beta] (GSK-3[beta]) for kinesin-1 and dynein function during axonal transport

Within axons, molecular motors transport essential components required for neuronal growth and viability. Although many levels of control and regulation must exist for proper anterograde and retrograde transport of vital proteins, little is known about these mechanisms. We previously showed that presenilin (PS), a gene involved in Alzheimer's disease (AD), influences kinesin-1 and dynein function in vivo. Here, we show that these PS-mediated effects on motor protein function are via a pathway that involves glycogen synthase kinase-3 beta (GSK-3 beta ). PS genetically interacts with GSK-3 beta in an activity-dependent manner. Excess of active GSK-3 beta perturbed axonal transport by causing axonal blockages, which were enhanced by reduction of kinesin-1 or dynein. These GSK-3 beta -mediated axonal defects do not appear to be caused by disruptions or alterations in microtubules (MTs). Excess of non-functional GSK-3 beta did not affect axonal transport. Strikingly, GSK-3 beta -activity-dependent axonal transport defects were enhanced by reduction of PS. Collectively, our findings suggest that PS and GSK-3 beta are required for normal motor protein function. Our observations propose a model, in which PS likely plays a role in regulating GSK-3 beta activity during transport. These findings have important implications for our understanding of the complex regulatory machinery that must exist in vivo and how this system is coordinated during the motility of vesicles within axons.