Inhibition of death-associated protein kinase 1 attenuates cis P-tau and neurodegeneration in traumatic brain injury.
Inhibition of death-associated protein kinase 1 attenuates cis P-tau and neurodegeneration in traumatic brain injury.
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抑制死亡相关蛋白激酶 1 可减轻创伤性脑损伤中的顺式 P-tau 和神经变性。
DOI：
10.1016/j.pneurobio.2021.102072
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发表时间：
2021-08
影响因子：
6.7
通讯作者：
Zhou XZ
中科院分区：
文献类型：
--
作者：
Kim N;Wang B;Koikawa K;Nezu Y;Qiu C;Lee TH;Zhou XZ
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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影响因子：
17.1
作者：
Goldstein LE;Fisher AM;Tagge CA;Zhang XL;Velisek L;Sullivan JA;Upreti C;Kracht JM;Ericsson M;Wojnarowicz MW;Goletiani CJ;Maglakelidze GM;Casey N;Moncaster JA;Minaeva O;Moir RD;Nowinski CJ;Stern RA;Cantu RC;Geiling J;Blusztajn JK;Wolozin BL;Ikezu T;Stein TD;Budson AE;Kowall NW;Chargin D;Sharon A;Saman S;Hall GF;Moss WC;Cleveland RO;Tanzi RE;Stanton PK;McKee AC
通讯作者：
McKee AC
影响因子：
5.3
作者：
Burda JE;Bernstein AM;Sofroniew MV
通讯作者：
Sofroniew MV
影响因子：
82.9
作者：
Holcomb, L;Gordon, MN;Duff, K
通讯作者：
Duff, K
影响因子：
7.6
作者：
Daugé, V;Sebret, A;Roques, BP
通讯作者：
Roques, BP
影响因子：
38.1
作者：
DeKosky, Steven T.;Blennow, Kaj;Ikonomovic, Milos D.;Gandy, Sam
通讯作者：
Gandy, Sam