Death-associated protein kinase 1 has a critical role in aberrant tau protein regulation and function
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Author
Kim, B M
You, M-H
Chen, C-H
Lee, S
Hong, Y
Kimchi, A
Zhou, X Z
Lee, T H
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https://doi.org/10.1038/cddis.2014.216Metadata
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Kim, B M, M-H You, C-H Chen, S Lee, Y Hong, A Kimchi, X Z Zhou, and T H Lee. 2014. “Death-associated protein kinase 1 has a critical role in aberrant tau protein regulation and function.” Cell Death & Disease 5 (5): e1237. doi:10.1038/cddis.2014.216. http://dx.doi.org/10.1038/cddis.2014.216.Abstract
The presence of tangles composed of phosphorylated tau is one of the neuropathological hallmarks of Alzheimer's disease (AD). Tau, a microtubule (MT)-associated protein, accumulates in AD potentially as a result of posttranslational modifications, such as hyperphosphorylation and conformational changes. However, it has not been fully understood how tau accumulation and phosphorylation are deregulated. In the present study, we identified a novel role of death-associated protein kinase 1 (DAPK1) in the regulation of the tau protein. We found that hippocampal DAPK1 expression is markedly increased in the brains of AD patients compared with age-matched normal subjects. DAPK1 overexpression increased tau protein stability and phosphorylation at multiple AD-related sites. In contrast, inhibition of DAPK1 by overexpression of a DAPK1 kinase-deficient mutant or by genetic knockout significantly decreased tau protein stability and abolished its phosphorylation in cell cultures and in mice. Mechanistically, DAPK1-enhanced tau protein stability was mediated by Ser71 phosphorylation of Pin1, a prolyl isomerase known to regulate tau protein stability, phosphorylation, and tau-related pathologies. In addition, inhibition of DAPK1 kinase activity significantly increased the assembly of MTs and accelerated nerve growth factor-mediated neurite outgrowth. Given that DAPK1 has been genetically linked to late onset AD, these results suggest that DAPK1 is a novel regulator of tau protein abundance, and that DAPK1 upregulation might contribute to tau-related pathologies in AD. Therefore, we offer that DAPK1 might be a novel therapeutic target for treating human AD and other tau-related pathologies.Other Sources
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4047864/pdf/Terms of Use
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