THE LOOP REGION OF PRESENILIN (PS) IS ESSENTIAL FOR GLYCOGEN SYNTHASE KINASE-3β (GSK-3β)-MEDIATED AXONAL TRANSPORT

Abstract

Neurons require intracellular transport of essential components for function and viability. Defects in axonal transport have been implicated in many neurodegenerative diseases, including Alzheimer's disease. Although multiple levels of regulation of motor protein function must exist for proper transport of components within axons, little is known about these mechanisms. One possible mechanism by which transport defects can occur is by improper regulation of molecular motors. Previous work has shown that reduction of Presenilin (PS) or Glycogen synthase kinase-3β (GSK-3β) stimulated the axonal motility of APP vesicles. Excess GSK-3β causes axonal transport defects and increased motor binding to membranes. Reduction of PS decreased active GSK-3β and motor binding to membranes, suggesting that PS and GSK-3β may function together during axonal transport. Since PS and GSK3β are known to interact in the β-Catenin pathway, we hypothesize that PS influences GSK3β activity for motor regulation. Using Drosophila genetics, we found that excess PS rescued GSK-3β mediated axonal blockages. Intriguingly, the catalytic region of PS (PS loop), which is known to bind to GSK3β, is essential for this rescue. Disruption of PS loop (PSΔE9) exacerbated GSK3β-mediated axonal blocks, while excess of PS loop suppressed it. Together, our observations suggest that functional PS containing an intact PS loop region is required to modulate GSK-3β-mediated roles during axonal transport. Perhaps, PS and GSK-3β physically interact to regulate motor activity during axonal transport similar to GSK-3β-mediated mechanisms in the β-Catenin pathway.