Exp Neurobiol.  2018 Jun;27(3):171-180. 10.5607/en.2018.27.3.171.

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

• Ho DH
• Je AR
• Lee H
• Son I
• Kweon HS
• Kim HG
• Seol W

• KMID: 2416244
• DOI: http://doi.org/10.5607/en.2018.27.3.171

Abstract

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.

Keyword

Parkinson's disease; LRRK2; microglia; neuroinflammation; mitochondrial fission; Drp1

MeSH Terms

Animals
Autophagy
Brain
Down-Regulation
Mice
Mice, Transgenic
Microglia*
Mitochondria
Mitochondrial Dynamics*
Neurons
Parkinson Disease
Phenotype
Phosphotransferases*
Phosphotransferases