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Inhibition of death-associated protein kinase 1 attenuates cis P-tau and neurodegeneration in traumatic brain injury.
Kim, Nami; Wang, Bin; Koikawa, Kazuhiro; Nezu, Yutaka; Qiu, Chenxi; Lee, Tae Ho; Zhou, Xiao Zhen.
Affiliation
  • Kim N; Division of Translational Therapeutics, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA; Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA; Division of Gerontology, Department o
  • Wang B; Division of Translational Therapeutics, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA; Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA; Broad Institute of Harvard and MIT, C
  • Koikawa K; Division of Translational Therapeutics, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA; Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA.
  • Nezu Y; Division of Translational Therapeutics, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA; Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA.
  • Qiu C; Division of Translational Therapeutics, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA; Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA; Broad Institute of Harvard and MIT, C
  • Lee TH; Division of Gerontology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA,02215, USA. Electronic address: tlee0813@fjmu.edu.cn.
  • Zhou XZ; Division of Translational Therapeutics, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA; Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA. Electronic address: xzhouenator@gmail
Prog Neurobiol ; 203: 102072, 2021 08.
Article in En | MEDLINE | ID: mdl-33979671
Traumatic brain injury (TBI) is the leading cause of mortality and disability in young people and may lead to the development of progressive neurodegeneration, such as that observed in chronic traumatic encephalopathy. We have recently found that the conformation-specific cis phosphorylated form of tau (cis P-tau) is a major early driver of neurodegeneration after TBI. However, not much is known about how cis P-tau is regulated in TBI. In this study, we demonstrated a novel critical role of death-associated protein kinase 1 (DAPK1) in regulating cis P-tau induction after TBI. We found that DAPK1 is significantly upregulated in mouse brains after TBI and subsequently promotes cis P-tau induction. Genetic deletion of DAPK1 in mice not only significantly decreases cis P-tau expression, but also effectively attenuates neuropathology development and rescues behavioral impairments after TBI. Mechanistically, DAPK1-mediated cis P-tau induction is regulated by the phosphorylation of Pin1 at Ser71, a unique prolyl isomerase known to control the conformational status of P-tau. Furthermore, pharmacological suppression of DAPK1 kinase activity dramatically decreases the levels of Pin1 phosphorylated at Ser71 as well as cis P-tau after neuronal stress. Thus, DAPK1 is a novel regulator of TBI that, in combination with its downstream targets, has a major impact on the development and/or outcome of TBI, and targeting DAPK1 might offer a potential therapeutic impact on TBI-related neurodegenerative diseases.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Brain Injuries, Traumatic Type of study: Risk_factors_studies Limits: Animals Language: En Journal: Prog Neurobiol Year: 2021 Document type: Article Country of publication:

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Brain Injuries, Traumatic Type of study: Risk_factors_studies Limits: Animals Language: En Journal: Prog Neurobiol Year: 2021 Document type: Article Country of publication: