Articles

  • the Korean Society for Brain and Neural Sciences

Article

Original Article

Exp Neurobiol 2018; 27(3): 171-180

Published online June 30, 2018

https://doi.org/10.5607/en.2018.27.3.171

© The Korean Society for Brain and Neural Sciences

LRRK2 Kinase Activity Induces Mitochondrial Fission in Microglia via Drp1 and Modulates Neuroinflammation

Dong Hwan Ho1†, A Reum Je2†, Haejin Lee2, Ilhong Son1,3, Hee-Seok Kweon2*,Hyung-Gun Kim4* and Wongi Seol1*

1InAm Neuroscience Research Center, Sanbon Medical Center, College of Medicine, Wonkwang University, Gunpo 15865, 2Electron Microscopy Research Center, Korea Basic Science Institute (KBSI), Daejeon 34133, 3Department of Neurology, Sanbon Medical Center, College of Medicine, Wonkwang University, Gunpo 15865, 4Department of Pharmacology, College of Medicine, Dankook University, Cheonan 31116, Korea

Correspondence to: *To whom correspondence should be addressed.
Hee-Seok Kweon, TEL: 82-43-240-5440, FAX: 82-42-865-3939
e-mail: hskweon@kbsi.re.kr
Hyung-Gun Kim, TEL: 82-41-550-3867, FAX: 82-41-551-3866
e-mail: hgkimm@dankook.ac.kr
Wongi Seol, TEL: 82-31-390-2411, FAX: 82-31-890-2414
e-mail: wseolha@gmail.com
These authors contributed equally

Received: June 1, 2018; Revised: June 28, 2018; Accepted: June 29, 2018

Leucine-rich repeat kinase 2 (LRRK2) mutations are the most common genetic cause of Parkinson's disease (PD). LRRK2 contains a functional kinase domain and G2019S, the most prevalent LRRK2 pathogenic mutation, increases its kinase activity. LRRK2 regulates mitochondria morphology and autophagy in neurons. LPS treatment increases LRRK2 protein level and mitochondrial fission in microglia, and down-regulation of LRRK2 expression or inhibition of its kinase activity attenuates microglia activation. Here, we evaluated the direct role of LRRK2 G2019S in mitochondrial dynamics in microglia. Initial observation of microglia in G2019S transgenic mice revealed a decrease in mitochondrial area and shortage of microglial processes compared with their littermates. Next, we elucidated the molecular mechanisms of these phenotypes. Treatment of BV2 cells and primary microglia with LPS enhanced mitochondrial fission and increased Drp1, a mitochondrial fission marker, as previously reported. Importantly, both phenotypes were rescued by treatment with GSK2578215A, a LRRK2 kinase inhibitor. Finally, the protein levels of CD68, an active microglia marker, Drp1 and TNF-α were significantly higher in brain lysates of G2019S transgenic mice compared with the levels in their littermates. Taken together, our data suggest that LRRK2 could promote microglial mitochondrial alteration via Drp1 in a kinase-dependent manner, resulting in stimulation of pro-inflammatory responses. This mechanism in microglia might be a potential target to develop PD therapy since neuroinflammation by active microglia is a major symptom of PD.

Graphical Abstract


Keywords: Parkinson’s disease, LRRK2, microglia, neuroinflammation, mitochondrial fission, Drp1