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Front. Cell. Neurosci. | doi: 10.3389/fncel.2018.00051

LRRK2 Contributes to Secondary Brain Injury through a p38/Drosha Signaling Pathway after Traumatic Brain Injury in Rats

 Rong Gao1*, Qin Rui2, Haibo Ni1, Fan Gao3, Baoqi Dang3, Di Li4 and  Gang Chen5
  • 1Department of Neurosurgery, Zhangjiagang First People's Hospital, China
  • 2Department of Laboratory, Zhangjiagang First People's Hospital, China
  • 3Department of Rehabilitation, Zhangjiagang City Hospital of Traditional Chinese Medicine, Nanjing University, China
  • 4Department of Translational Medicine Center, Zhangjiagang First People's Hospital, China
  • 5Department of Neurosurgery & Brain and Nerve Research Laboratory, First Affiliated Hospital of Soochow University, China

Leucine-rich repeat kinase 2 (LRRK2) is widely expressed in the brain and exerts neurotoxicity in Parkinson's disease. The p38/Drosha signaling activation has been reported to increase cell death under stress. This study was designed to investigate the potential role and mechanism of LRRK2 in secondary brain injury after traumatic brain injury (TBI). A total of 130 male Sprague-Dawley rats were examined using a weight-drop model of TBI. The rats received the specific LRRK2 inhibitor PF-06447475 or LRRK2 pDNA alone or in combination with Drosha pDNA. Real-time PCR, Western blot, immunofluorescence, neuronal apoptosis, brain water content, and neurological score analyses were conducted. Our results showed that after TBI, endogenous LRRK2 expression and p38 phosphorylation were increased, whereas Drosha expression was inhibited. Administration of the LRRK2 inhibitor PF-06447475 significantly reduced neuronal apoptosis, brain water content, and blood-brain barrier permeability 12 h after TBI and ameliorated neurological deficits 72 h after TBI, which was concomitant with decreased p38 phosphorylation and increased Drosha expression. Conversely, LRRK2 overexpression induced the opposite effect. Moreover, the neurotoxic effects of LRRK2 on TBI were also eliminated by Drosha overexpression. Altogether, these findings demonstrate the importance of TBI-induced LRRK2 upregulation during the induction of post-traumatic neurological injury, which may be partially mediated through a p38/Drosha signaling pathway.

Keywords: LRRK2, p38, Drosha, Traumatic Brain Injury, Secondary brain injury

Received: 26 Oct 2017; Accepted: 15 Feb 2018.

Edited by:

Arthur Liesz, Ludwig-Maximilians-Universität München, Germany

Reviewed by:

Bogdan A. Stoica, University of Maryland, Baltimore, United States
Carmelo Sgobio, Deutsche Zentrum für Neurodegenerative Erkrankungen (DZNE), Germany  

Copyright: © 2018 Gao, Rui, Ni, Gao, Dang, Li and Chen. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Rong Gao, Zhangjiagang First People's Hospital, Department of Neurosurgery, Zhangjiagang, China,