A DNA damage-activated checkpoint kinase phosphorylates tau and enhances tau-induced neurodegeneration

Abstract

Hyperphosphorylation of the microtubule associated protein tau is detected in the brains of individuals with a range of neurodegenerative diseases including Alzheimer's disease (AD). An imbalance in phosphorylation and/or dephosphorylation of tau at disease-related sites has been suggested to initiate the abnormal metabolism and toxicity of tau in disease pathogenesis. However, the mechanisms underlying abnormal phosphorylation of tau in AD are not fully understood. Here, we show that the DNA damage-activated Checkpoint kinase 2 (Chk2) is a novel tau kinase and enhances tau toxicity in a transgenic Drosophila model. Overexpression of Drosophila Chk2 increases tau phosphorylation at Ser262 and enhances tau-induced neurodegeneration in transgenic flies expressing human tau. The non-phosphorylatable Ser262Ala mutation abolishes Chk2-induced enhancement of tau toxicity, suggesting that the Ser262 phosphorylation site is involved in the enhancement of tau toxicity by Chk2. In vitro kinase assays revealed that human Chk2 and a closely related checkpoint kinase 1 (Chk1) directly phosphorylate human tau at Ser262. We also demonstrate that Drosophila Chk2 does not modulate the activity of the fly homolog of microtubule affinity regulating kinase, which has been shown to be a physiological tau Ser262 kinase. Since accumulation of DNA damage has been detected in the brains of AD patients, our results suggest that the DNA damage-activated kinases Chk1 and Chk2 may be involved in tau phosphorylation and toxicity in the pathogenesis of AD.

The Power and Richness of Modelling Tauopathies in Drosophila

“…This is the only case of NFT-like aggregate formation other than in glia as described above. In a similar independent study, over-expression of Drosophila Chk2 kinase enhanced the toxicity of WT Tau, but NFTs or other type of aggregates were not reported in this case [97].…”

Neuroprotective Functions for the Histone Deacetylase SIRT6

“…Tau is phosphorylated by several kinases including CHK2 and GSK3 (Martin et al, 2013), known to be activated by DNA damage (Iijima-Ando et al, 2010; Ngok-Ngam et al, 2013; Watcharasit et al, 2002). While no changes were observed in CHK2 activation, we observed decreased levels of phospho-GSK3, a marker for increased GSK3 activity (Fig.…”

Aging and amyloid beta-induced oxidative DNA damage and mitochondrial dysfunction in Alzheimer's disease: Implications for early intervention and therapeutics

“…Then hyperphospharylated tau eventually induces neurodegeneration and neuron loss by disrupting neuronal cytoskeleton. It has been shown that DNA damage-activated kinases such as Chk1 and Chk2 may be involved in tau phosphorylation and toxicity in the pathogenesis of AD [73]. Tau may also be a crucial partner of Aβ, enhance the pathology of Aβ, as well as Tau-Aβ interplay a role in AD.…”