Functional Implications of Glycogen Synthase Kinase‐3‐Mediated Tau Phosphorylation

Abstract

Tau is primarily a neuronal microtubule-associated protein that has functions related to the stabilisation of microtubules. Phosphorylation of tau is an important dynamic and regulatory element involved in the binding of tau to tubulin. Thus, highly phosphorylated tau is more likely to be present in the cytosolic compartment of neurons, whereas reduced phosphate burden allows tau to bind to and stabilise the microtubule cytoskeleton. Highly phosphorylated forms of tau are deposited in the brain in a range of neurodegenerative disorders including Alzheimer's disease, progressive supranuclear palsy, and frontotemporal lobar degeneration associated with Pick bodies. A key candidate kinase for both physiological and pathological tau phosphorylation is glycogen synthase kinase-3 (GSK-3). Multiple phosphorylation sites have been identified on tau exposed to GSK-3 in vitro and in cells. In this review, we highlight recent data suggesting a role for GSK-3 activity on physiological tau function and on tau dysfunction in neurodegenerative disease.

Tau-induced neurodegeneration: mechanisms and targets

“…GSK-3 has two isoforms, GSK-3α and GSK-3β, which share 85% sequence identity [32] . In vitro, GSK-3 phosphorylates tau on ~40 Ser/Thr residues, and 348 CK1 is the only other kinase comparable to GSK-3 in that it phosphorylates tau residues in similar numbers [31] . GSK-3 phosphorylation reduces the capability of tau to promote microtubule assembly in vitro and in cells [33,34] .…”

“…Hyperphosphorylation of tau protein causes oligomerization and aggregation, eventually leading to paired helical filaments (PHFs) which are characteristic of pre-tangles in the neurons of AD patients [29] . In contrast, dephosphorylation of tau increases binding to tubulin, promotes microtubule growth, and normalizes the microtubule cytoskeleton [30,31] . …”

“…CK1 is the only other kinase comparable to GSK-3 in that it phosphorylates tau residues in similar numbers [31] . GSK-3 phosphorylation reduces the capability of tau to promote microtubule assembly in vitro and in cells [33,34] .…”

Prostate-derived Sterile 20-like Kinases (PSKs/TAOKs) Phosphorylate Tau Protein and Are Activated in Tangle-bearing Neurons in Alzheimer Disease

“…Phosphorylated residues are located in the tau microtubule-binding domain and in the regions flanking this domain, and more than half of these modified tau residues are also found in PHF-tau extracted from AD brains (30). PSKs are also activated catalytically in regions of the brain that are susceptible to AD pathology and are present in intraneuronal NFTs, neuropil threads, and granulovacuolar degeneration bodies where tau is also phosphorylated.…”

Specific Serine-Proline Phosphorylation and Glycogen Synthase Kinase 3β-directed Subcellular Targeting of Stathmin 3/Sclip in Neurons

“…6A). To test the efficacy of the two inhibitors on GSK-3␤ activity in vivo, we monitored the amount of phosphorylation of Tau, a well known GSK-3␤ substrate (51), by immunoblotting treated cell extracts with a specific antibody directed to Tau phosphorylated at serine 199. As expected, the phosphorylation of Tau decreased upon pharmacological treatment with the GSK-3␤ inhibitors, dose dependently in the 10 M range in vivo (Fig.…”