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Death-associated protein kinase 1 has a critical role in aberrant tau protein regulation and function.

 B M Kim  ;  M H You  ;  C H Chen  ;  S Lee  ;  Y Hong  ;  Y Hong  ;  A Kimchi  ;  X Z Zhou  ;  T H Lee 
 CELL DEATH & DISEASE, Vol.5(e1237) : 1-7, 2014 
Journal Title
Issue Date
Age Factors ; Alzheimer Disease/enzymology* ; Alzheimer Disease/genetics ; Alzheimer Disease/pathology ; Animals ; Brain/enzymology* ; Brain/pathology ; Case-Control Studies ; Death-Associated Protein Kinases/deficiency ; Death-Associated Protein Kinases/genetics ; Death-Associated Protein Kinases/metabolism* ; HEK293 Cells ; HeLa Cells ; Humans ; Mice ; Mice, Knockout ; Mutation ; NIH 3T3 Cells ; NIMA-Interacting Peptidylprolyl Isomerase ; Neurites/enzymology ; Neurites/pathology ; Neurons/enzymology* ; Neurons/pathology ; PC12 Cells ; Peptidylprolyl Isomerase/deficiency ; Peptidylprolyl Isomerase/genetics ; Phosphorylation ; Protein Stability ; RNA Interference ; Rats ; Time Factors ; Transfection ; tau Proteins/genetics ; tau Proteins/metabolism*
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.
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5. Research Institutes (연구소) > Yonsei Integrative Research Institute for Cerebral & Cardiovascular Disease (뇌심혈관질환융합연구사업단) > 1. Journal Papers
Yonsei Authors
Kim, Byeong Mo(김병모) ORCID logo https://orcid.org/0000-0002-0582-3132
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