김남이 (Beth Israel Deaconess Medical Center, Harvard Medical School) | 한빛사논문 > 한빛사

한빛사논문

조회1,338

Beth Israel Deaconess Medical Center, Harvard Medical School

CV File 141 kb

Prog. Neurobiol., Available online 9 May 2021, 102072 | https://doi.org/10.1016/j.pneurobio.2021.102072 Inhibition of Death-associated Protein Kinase 1 Attenuates Cis P-tau and Neurodegeneration in Traumatic Brain Injury

Nami Kim^a,b,c, Bin Wang^a,b,d, Kazuhiro Koikawa^a,b, Yutaka Nezu^a,b, Chenxi Qiu^a,b,d, Tae Ho Lee^c,1,*, Xiao Zhen Zhou^a,b,d,1,*

^aDivision of Translational Therapeutics, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA
^bCancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA
^cDivision of Gerontology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA,02215, USA
^dBroad Institute of Harvard and MIT, Cambridge, MA, 02142, USA

¹These authors jointly supervised this work.

^*Corresponding author

Abstract

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.

Keywords : cis phosphorylated tau (cis P-tau), cistauosis, death-associated protein kinase 1 (DAPK1), Pin1, traumatic brain injury (TBI)

논문정보

형식Research article
게재일2021년 05월 (BRIC 등록일 2021-05-13)
연구진국외 연구진
분야 생명과학 > 신경생물학

댓글 작성 로그인

CV 열람하기

연락처 보기