期刊
PROGRESS IN NEUROBIOLOGY
卷 203, 期 -, 页码 -出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.pneurobio.2021.102072
关键词
Cistauosis; Death-associated protein kinase 1 (DAPK1); Pin1; Traumatic brain injury (TBI); Cis phosphorylated tau (Cis P-tau)
资金
- BrightFocus Foundation [A2017180S]
- NIH [R01AG055559]
- National Football League grant
It has been shown that death-associated protein kinase 1 (DAPK1) plays a critical role in regulating the induction of cis phosphorylated form of tau protein (cis P-tau) after traumatic brain injury (TBI). DAPK1 mediates cis P-tau induction through phosphorylation of Pin1 at Ser71. Genetic deletion of DAPK1 reduces cis Ptau expression, attenuates neuropathology development, and rescues behavioral impairments after TBI.
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 Ptau 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 Ptau 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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