Brain injury induces HIF-1α-dependent transcriptional activation of LRRK2 that exacerbates brain damage

Title
Brain injury induces HIF-1α-dependent transcriptional activation of LRRK2 that exacerbates brain damage
Authors
류훈최환근배윤희주혜진배진현허송욱고은화허은미부영민이병대Seung Jae Hyeon
Keywords
Leucine-rich repeat kinase 2 (LRRK2); traumatic brain injury (TBI); hypoxia-inducible factor (HIF)-1α
Issue Date
2018-11
Publisher
CELL DEATH & DISEASE
Citation
VOL 9, NO 11-1125-19
Abstract
Leucine-rich repeat kinase 2 (LRRK2), originally identified as a causative genetic factor in Parkinson’s disease, is now associated with a number of pathologies. Here, we show that brain injury induces a robust expression of endogenous LRRK2 and suggest a role of LRRK2 after injury. We found that various in vitro and in vivo models of traumatic brain injury (TBI) markedly enhanced LRRK2 expression in neurons and also increased the level of hypoxia-inducible factor (HIF)-1α. Luciferase reporter assay and chromatin immunoprecipitation revealed direct binding of HIF-1α in LRRK2 proximal promoter. We also found that HIF-1α-dependent transcriptional induction of LRRK2 exacerbated neuronal cell death following injury. Furthermore, application of G1023, a specific, brain-permeable inhibitor of LRRK2, substantially prevented brain tissue damage, cell death, and inflammatory response and alleviated motor and cognitive defects induced by controlled cortical impact injury. Together, these results suggest HIF-1α-LRRK2 axis as a potential therapeutic target for brain injury.
URI
http://pubs.kist.re.kr/handle/201004/68910
ISSN
2041-4889
Appears in Collections:
KIST Publication > Article
Files in This Item:
There are no files associated with this item.
Export
RIS (EndNote)
XLS (Excel)
XML


qrcode

Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.

BROWSE