Further understanding of tau phosphorylation: implications for therapy

Abstract

Tau is a brain microtubule-associated protein that regulates microtubule structure and function. Prominent tau neurofibrillary pathology is a common feature in a number of neurodegenerative disorders collectively referred to as tauopathies, the most common of which is Alzheimer's disease. Beyond its classical role as a microtubule-associated protein, recent advances in our understanding of tau cellular functions have unveiled novel important tau cellular functions that may also play a pivotal role in pathogenesis and render novel targets for therapeutic intervention. Regulation of tau behavior and function under physiological and pathological conditions is mainly achieved through post-translational modifications, especially phosphorylation, which has significant implications for the development of novel therapeutic approaches in a number of neurodegenerative disorders.

Lamin Dysfunction Mediates Neurodegeneration in Tauopathies

“…We next determined if Lamin invaginations coincide with pathological tau. Tau phosphorylation is a well-characterized pathogenic event in Alzheimer’s disease and related tauopathies [12]. 86% of nuclei containing Lamin invaginations in tau R406W transgenic Drosophila were positive for tau phosphorylated at serine 214, a disease-associated tau phosphopepitope (Figure 1D).…”

Tau physiology and pathomechanisms in frontotemporal lobar degeneration

“…However, therapeutic modulation of PP2A is challenging because of its multimeric structure and the different intracellular signalling pathways in which it has a role (Kamat et al . ; Medina and Avila ).…”

“…It is thought that one reason for the abnormal increase in tau phosphorylation might be an imbalance in the activity or regulation of kinases and phosphatases. Among the kinases, glycogen synthase-3 (GSK3), cyclin-dependent kinase 5, the MAPK family composed of p38, extracellular-regulated kinase and c-Jun N-terminal kinase, and microtubule-affinity regulating kinase (MARK) have been shown to have a role and are considered as candidates for therapy (reviewed in Lee et al 2011;Tell and Hilgeroth 2013;Medina and Avila 2015). Interestingly, tau phosphorylation pathways seem to be evolutionarily conserved, as revealed by a study of 2N4R human tau overexpression in Drosophila, that described tau hyperphosphorylation via the involvement of the GSK3 homologue shaggy or Sgg (Jackson et al 2002).…”

“…PP2A is the major brain phosphatase of tau (Gong et al 2000), and reduced PP2A activity was found to cause hyperphosphorylation and compartmentalization of tau in mice (Kins et al 2001). However, therapeutic modulation of PP2A is challenging because of its multimeric structure and the different intracellular signalling pathways in which it has a role (Kamat et al 2014;Medina and Avila 2015).…”

The use of human neurons for novel drug discovery in dementia research

“…Traditionally these have been developed in animal models of disease and have attempted to counteract pathogenic changes in tau identified in post-mortem brain tissue. They include approaches to reduce tau phosphorylation 69 , reduce tau aggregation 70 and clear toxic tau oligomers and tangles 71 . Additionally some studies have explored the utility of microtubule stabilising agents to compensate for loss of microtubule binding function 72 .…”