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

Abstract

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-3β (GSK-3β). PS genetically interacts with GSK-3β in an activity-dependent manner. Excess of active GSK-3β perturbed axonal transport by causing axonal blockages, which were enhanced by reduction of kinesin-1 or dynein. These GSK-3β-mediated axonal defects do not appear to be caused by disruptions or alterations in microtubules (MTs). Excess of non-functional GSK-3β did not affect axonal transport. Strikingly, GSK-3β-activity-dependent axonal transport defects were enhanced by reduction of PS. Collectively, our findings suggest that PS and GSK-3β are required for normal motor protein function. Our observations propose a model, in which PS likely plays a role in regulating GSK-3β 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.

GSK3 and KIF5 regulate activity-dependent sorting of gephyrin between axons and dendrites

“…The kinase GSK3 contributes to both mechanisms. In fact, GSK3 regulates KIF5 transport via phosphorylation of kinesin light chain (Cantuti Castelvetri et al, 2013;Dolma et al, 2014;Morfini et al, 2004) and controls gephyrin clustering via phosphorylation of gephyrin S270 (Tyagarajan et al, 2011(Tyagarajan et al, , 2013. Our data show that serine 270 is not involved in axonal missorting of gephyrin, whereas functional blockade of GSK3 and KIF5 normalizes axonal targeting of gephyrin.…”

“…Since GSK3 is known to regulate kinesin-1 (KIF5) (Dolma et al, 2014), mainly through phosphorylation of kinesin light (Maas et al, 2009), was coexpressed with tomato-gephyrin in the presence of 20 M AMPA (Fig. 4A and B and Supplementary Fig.…”

The Key Roles of GSK-3β in Regulating Mitochondrial Activity

“…TRAK1 is a key protein connecting the MOM protein Miro to the molecular motors kinesin and dynein [32]. Inconsistently, GSK-3β has been reported to be required for normal functions of motor proteins kinesin and dynein [33]. GSK-3β physically binds to TRAK1, together with DISC1 and NDE1, to form a complex, promoting mitochondrial trafficking in cultured hippocampal neurons [34].…”

Linking mitochondrial dysfunction, metabolic syndrome and stress signaling in Neurodegeneration

“…Likewise, impairment in the functional expression of Peroxisome proliferator-activated receptor gamma co-activator 1-alpha (PGC-1α), a master regulator of mitochondrial biogenesis is also involved in AD progression [26]. Furthermore, mitochondrial axonal transport is profoundly affected by mutations in Presenilin 1, most likely by affecting phosphorylation of kinesin light chain through effects on GSK3β [27]. Moreover, accumulation of Aβ in the protein import channels of mitochondria has currently been reported in AD brains that are responsible for mitochondrial dysfunction that potentiate neuronal and synaptic stress thereby increasing the severity of disease [28].…”

“…Moreover, it is proved to be neuroprotective in HD and stroke models AD and HD [114] Melatonin Improves the ultrastructure of mitochondria in the neurons of the CA1 region and prevents the decrease in the mitochondria-occupied portion of the neuronal volume in AD AD [115] Mori Fructus (ME) Decreases mitochondria depolarization, Cyt c release from mitochondria and caspase-3 activation induced by Aβ (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35) toxicity in the mouse hippocampus AD [116] Erythropoietin (EPO) Alleviates the Aβ-induced mitochondrial dysfunction and apoptosis in brain AD [117] Linagliptin…”