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

Experimental Neurobiology
Dong Hwan HoWongi Seol

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 ...Continue Reading

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Citations

May 30, 2019·Experimental Neurobiology·Wongi SeolIlhong Son
Jun 9, 2019·Journal of Neuroinflammation·Chris RudykUNKNOWN CLINT membership
Jun 9, 2020·Frontiers in Neuroscience·Rebecca L WallingsMalú Gámez Tansey
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Jul 8, 2021·Experimental Neurobiology·Hyejung KimWongi Seol
Jun 14, 2019·Experimental Cell Research·Xiaoling ZhangXiaoqun Ge
Sep 28, 2021·Frontiers in Cell and Developmental Biology·Katharina E RosenbuschArjan Kortholt
Apr 14, 2019·Life Sciences·Chand RazaNoor Ul Ain Shakeel

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Methods Mentioned

BETA
GTPase
enzyme-linked immunosorbent assay
transgenic
ELISA
transmission electron microcopy
confocal microscopy

Software Mentioned

Mito
Image J
Prism
GraphPad
- Morphology Macro

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