Bae, Yun-Hee Joo, Hyejin Bae, Jinhyun Hyeon, Seung Jae Her, Song Ko, Eunhwa Choi, Hwan Geun Ryu, Hoon Hur, Eun-Mi Bu, Youngmin Lee, Byoung Dae 2024-01-19T21:30:59Z 2024-01-19T21:30:59Z 2021-09-05 2018-11-12 2041-4889 https://pubs.kist.re.kr/handle/201004/120685 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)-1 alpha. Luciferase reporter assay and chromatin immunoprecipitation revealed direct binding of HIF-1 alpha in LRRK2 proximal promoter. We also found that HIF-1 alpha-dependent transcriptional induction of LRRK2 exacerbated neuronal cell death fol lowing 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 control led cortical impact injury. Together, these results suggest HIF-1 alpha-LRRK2 axis as a potential therapeutic target for brain injury. English NATURE PUBLISHING GROUP INDUCIBLE FACTOR (HIF)-1-ALPHA GENOME-WIDE ASSOCIATION PARKINSONS-DISEASE KINASE-ACTIVITY DOPAMINERGIC-NEURONS SIGNALING PATHWAY CORTICAL-NEURONS IN-VITRO EXPRESSION PHOSPHORYLATION Brain injury induces HIF-1 alpha-dependent transcriptional activation of LRRK2 that exacerbates brain damage Article 10.1038/s41419-018-1180-y 1 CELL DEATH & DISEASE, v.9 CELL DEATH & DISEASE 9 scie scopus 000449803600001 2-s2.0-85065266134 Cell Biology Cell Biology Article INDUCIBLE FACTOR (HIF)-1-ALPHA GENOME-WIDE ASSOCIATION PARKINSONS-DISEASE KINASE-ACTIVITY DOPAMINERGIC-NEURONS SIGNALING PATHWAY CORTICAL-NEURONS IN-VITRO EXPRESSION PHOSPHORYLATION Leucine-rich repeat kinase 2 (LRRK2) traumatic brain injury (TBI) hypoxia-inducible factor (HIF)-1α