Role of tau phosphorylation by glycogen synthase kinase-3β in the regulation of organelle transport

Abstract

Anterograde organelle transport is known to be inhibited by overexpression of the microtubule-associated protein tau in cultured cells. However, the molecular mechanism regulating this function of tau protein has not previously been understood. We found that in PC12 cells treated with NGF or fibroblast growth factor-2, glycogen synthase kinase-3β and tau were upregulated simultaneously from around day 2 of differentiation, with increasing glycogen synthase kinase-3-mediated tau phosphorylation. This phosphorylation did not alter tau's ability to bind to microtubules but appeared to be required for the maintenance of the anterograde organelle transport in differentiated cells. Lithium, alsterpaullone or valproate, three independent glycogen synthase kinase-3 inhibitors, but not butyrolactone 1, an inhibitor of cyclin-dependent protein kinases, induced mitochondrial clustering in association with tau dephosphorylation. In CHO cells transfected with human tau441, mitochondrial clustering was found in cells in which tau was unphosphorylated. These findings raise the possibility that the phosphorylation of tau by glycogen synthase kinase-3 might be involved in the regulation of organelle transport.

Nerve growth factor as a paradigm of neurotrophins related to Alzheimer's disease

“…The phosphorylation state of tau-which critically controls its physiopathology leading to selfaggregation and/or reduced assembly and stability of microtubules used as tracks for axonal trafficking (Stoothoff et al, 2005)-is also regulated by NGF deprivation in vitro (Nuydens et al, 1997;Shelton and Johnson, 2001) as well as in vivo Capsoni et al, 2002a,b). Moreover, since tau controls the bidirectionality of axonal motor-driven transport in a concentration-dependent manner and differentially modulates the kinesin and dynein activity along microtubule tracks (Dixit et al, 2008), defective intracellular trafficking of cargoes, including NTFs, could be due to an increased expression level of this protein (Ebneth et al, 1998;Stamer et al, 2002;Mandelkow et al, 2003) or to its altered intracellular localization (Thies et al, 2007) or hyperphosphorylation (Tatebayashi et al, 2004;Alonso et al, 1997). To this regard, the finding that the retrograde transport of I-125-NGF and activated Trk receptors is inhibited by colchicine-a drug that interferes with the polymerization of microtubules (Watson et al, 1999;Sandow et al, 2000)-suggests that an altered function of tau protein may account for age-related deficiency of long-range NTF signaling in cholinergic neurons.…”

Does the term ‘trophic’ actually mean anti-amyloidogenic? The case of NGF

“…60,61 Furthermore, a caspase(s)-mediated truncation of N-terminal tau domain, which possibly interacts with dynactin/dynein motor complex, 62 also occurs in vitro and in vivo on NGF signaling interruption. 48 GSK3b-mediated tau phosphorylation is associated with a proper anterograde organelle transport 63 in NGF-dependent differentiated PC12, and synthetic Ab peptides cause a GSK3b-mediated impairment of mitochondrial transport in hippocampal cultured neurons. 64 Finally, a mislocalization of pThr 231-tau protein and GSK3b in basal forebrain cholinergic neurons of aged rats is causally linked to an in vivo defective retrograde axonal transport.…”

Activation of GSK‐3 disrupts cholinergic homoeostasis in nucleus basalis of Meynert and frontal cortex of rats

“…Elevated tau phosphorylation decreases its microtubule binding and bundling and increases the number of motile tau particles, which affects the axonal transport 37. The tau phosphorylation mediated by GSK3β is associated with proper anterograde transport 38. Therefore, we speculate that hyperphosphorylation of tau induced by GSK‐3 activation may be involved in the impaired axonal transport of ChAT (Fig.…”