Dissociation of tau toxicity and phosphorylation: role of GSK-3β, MARK and Cdk5 in a Drosophila model

Abstract

Hyperphosphorylation of tau at multiple sites has been implicated in the formation of neurofibrillary tangles in Alzheimer’s disease; however, the relationship between toxicity and phosphorylation of tau has not been clearly elucidated. Putative tau kinases that play a role in such phosphorylation events include the proline-directed kinases glycogen synthase kinase-3β (GSK-3β) and cyclin-dependent kinase 5 (Cdk5), as well as nonproline-directed kinases such as microtubule affinity-regulating kinase (MARK)/PAR-1; however, whether the cascade of events linking tau phosphorylation and neurodegeneration involves sequential action of kinases as opposed to parallel pathways is still a matter of controversy. Here, we employed a well-characterized Drosophila model of tauopathy to investigate the interdependence of tau kinases in regulating the phosphorylation and toxicity of tau in vivo. We found that tau mutants resistant to phosphorylation by MARK/PAR-1 were indeed less toxic than wild-type tau; however, this was not due to their resistance to phosphorylation by GSK-3β/Shaggy. On the contrary, a tau mutant resistant to phosphorylation by GSK-3β/Shaggy retained substantial toxicity and was found to have increased affinity for microtubules compared with wild-type tau. The fly homologs of Cdk5/p35 did not have major effects on tau toxicity or phosphorylation in this model. These data suggest that, in addition to tau phosphorylation, microtubule binding plays a crucial role in the regulation of tau toxicity when misexpressed. These data have important implications for the understanding and interpretation of animal models of tauopathy.

Untangling the role of tau in Alzheimer’s disease: A unifying hypothesis

“…Many of these kinases have also been shown to play important roles in regulating mitotic activity and/or early stages of neuronal differentiation [131,[155][156][157][158]. The reactivation of genes associated with cell cycle re-entry and early stages of neurodifferentiation [86][87][88][89][90] It has generally been assumed that the formation of tau aggregates occurs directly via oligomerization to granular aggregates or "pre-tangles" in the cytosol [130,[146][147][148] although this process has not been extensively characterized in cellular tauopathy models.…”

Interaction Between Eye Pigment Genes and Tau-Induced Neurodegeneration inDrosophila melanogaster

“…S202/T205 phosphorylation does not correlate well with severity of tau phenotypes in our model. Recent studies using tau constructs resistant to phosphorylation also demonstrated uncoupling of tau phosphorylation at S202/T205 and toxicity (Steinhilb et al 2007;Chatterjee et al 2009), suggesting that other mechanisms, such as increased microtubule binding affinity by tau (Chatterjee et al 2009), or alternatively, tau oligomerization (Kayed and Jackson 2009), may have more direct toxic effects. 2.…”

“…GSK-3b may also modulate tau-induced toxicity by regulating the activity of the kinase partitioning defective 1 (par-1) (Timm et al 2008). PAR-1, also known as MARK (Microtubule-Associated Protein/Microtubule Affinity Regulating Kinase), is another known tau kinase (Drewes et al 1995) shown to modulate tau-induced toxicity; however, reports differ as to whether PAR-1 activity enhances (Nishimura et al 2004;Chatterjee et al 2009) or suppresses (Shulman and Feany 2003;Chen et al 2007;Thies and Mandelkow 2007) tauinduced toxicity. 4.…”

Tau-induced neurodegeneration: mechanisms and targets

“…Overexpression of the fl y homolog of MARK (dMARK) causes an increase in tau phosphorylation at Ser262/356 which increases tau toxicity [43,44] .…”