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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Neurosci. | doi: 10.3389/fnins.2019.00905

Leucine-Rich Repeat Kinase 2 is Associated with Activation of the Paraventricular Nucleus of the Hypothalamus and Stress-Related Gastrointestinal Dysmotility

 Tatsunori Maekawa1, 2*,  Hiromichi Tsushima3,  Fumitaka Kawakami1, 2, Rei Kawashima1, 2,  Masaru Kodo1, 2 and Takafumi Ichikawa1, 2
  • 1School of Allied Health Sciences, Kitasato University, Japan
  • 2Department of Biochemistry, Graduate School of Medical Sciences, Kitasato University (KUGSMS), Japan
  • 3Department of Behavioral Medicine, Tohoku University School of Medicine, Japan

Leucine-rich repeat kinase 2 (LRRK2) is a molecule associated with familial and sporadic Parkinson’s disease. It regulates many central neuronal functions such as cell proliferation, apoptosis, autophagy, and axonal extension. Recently, it has been revealed that LRRK2 is related to anxiety/depression-like behavior, implying an association between LRRK2 and stress. In the present study, we investigated for the first time the stress pathway and its relationship to gastrointestinal motility in LRRK2-knockout (KO) mice. The mice were subjected to acute restraint stress, and analyzed for activation of the paraventricular nucleus of the hypothalamus (PVN) using an immunohistochemical approach. Phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) was assessed by Western blotting. The KO mice showed a lower number of c-Fos-positive cells and disruption of the ERK signaling pathway in the PVN in the presence of restraint stress. Stress responses in terms of both upper and lower gastrointestinal motility were alleviated in the mice, accompanied by lower c-Fos immunoreactivity in enteric excitatory neurons. Our present findings suggest that LRRK2 is a newly recognized molecule regulating the stress pathway in the PVN, playing a role in stress-related gastrointestinal dysmotility.

Keywords: LRRK2, gut dysmotility, stress, signaling, signaling / signaling pathways, Paraventricular (PVN)

Received: 15 Feb 2019; Accepted: 13 Aug 2019.

Edited by:

Pascal Derkinderen, Université de Nantes, France

Reviewed by:

Isabella Russo, University of Brescia, Italy
Jean-Marc Taymans, Institut National de la Santé et de la Recherche Médicale (INSERM), France  

Copyright: © 2019 Maekawa, Tsushima, Kawakami, Kawashima, Kodo and Ichikawa. 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(s) 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: PhD. Tatsunori Maekawa, School of Allied Health Sciences, Kitasato University, Kanagawa, Japan, maekawa@kitasato-u.ac.jp