Death-associated protein kinase 1 has a critical role in aberrant tau protein regulation and function.
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.
Division of Gerontology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
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Kim
Division of Gerontology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
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You
Division of Hematology/Oncology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
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Chen
1] Department of Rehabilitation Science, Graduate School of Inje University, Gimhae, Korea [2] Cardiovascular & Metabolic Disease Center, College of Biomedical Science & Engineering, Inje University, Gimhae, Korea.
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Lee
1] Department of Rehabilitation Science, Graduate School of Inje University, Gimhae, Korea [2] Cardiovascular & Metabolic Disease Center, College of Biomedical Science & Engineering, Inje University, Gimhae, Korea.
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Hong
1] Division of Gerontology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA [2] Department of Rehabilitation Science, Graduate School of Inje University, Gimhae, Korea [3] Cardiovascular & Metabolic Disease Center, College of Biomedical Science & Engineering, Inje University, Gimhae, Korea.
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Hong
Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
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Kimchi
Division of Hematology/Oncology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
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Zhou
Division of Gerontology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
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Lee
D000367:Age Factors; D000544:Alzheimer Disease / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D000818:Animals; D001921:Brain / Q000201:enzymology* / Q000473:pathology; D016022:Case-Control Studies; D064550:Death-Associated Protein Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D041681:NIH 3T3 Cells; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D016501:Neurites / Q000201:enzymology / Q000473:pathology; D009474:Neurons / Q000201:enzymology* / Q000473:pathology; D016716:PC12 Cells; D019696:Peptidylprolyl Isomerase / Q000172:deficiency / Q000235:genetics; D010766:Phosphorylation; D055550:Protein Stability; D034622:RNA Interference; D051381:Rats; D013997:Time Factors; D014162:Transfection; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
C054369:MAPT protein, human; C558298:Mapt protein, mouse; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D016875:tau Proteins; C579096:DAPK1 protein, human; C579106:Dapk1 protein, mouse; D064550:Death-Associated Protein Kinases; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase; C000606850:Pin1 protein, mouse