PT  - JOURNAL ARTICLE
AU  - C.G. Weindel
AU  - S.L. Bell
AU  - T. Huntington
AU  - K. Vail
AU  - R. Srinivasan
AU  - K.L. Patrick
AU  - R.O. Watson
TI  - LRRK2 regulates innate immune responses and neuroinflammation during <em>Mycobacterium tuberculosis</em> infection
AID  - 10.1101/699066
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 699066
4099  - http://biorxiv.org/content/early/2019/07/11/699066.short
4100  - http://biorxiv.org/content/early/2019/07/11/699066.full
AB  - Despite many connections between mutations in leucine-rich repeat kinase 2 (LRRK2) and susceptibility to mycobacterial infection, we know little about its function outside of the brain, where it is studied in the context of Parkinson’s Disease (PD). Here, we report that Lrrk2 controls peripheral macrophages and brain-resident glial cells’ ability to respond to and express inflammatory molecules. LRRK2 KO macrophages express elevated basal levels of type I interferons, resulting from defective purine metabolism, mitochondrial damage, and engagement of mitochondrial DNA with the cGAS DNA sensing pathway. While LRRK2 KO mice can control Mycobacterium tuberculosis (Mtb) infection, they exhibit exacerbated lung inflammation and altered activation of glial cells in PD-relevant regions of the brain. These results directly implicate Lrrk2 in peripheral immunity and support the “multiple-hit hypothesis” of neurodegenerative disease, whereby infection coupled with genetic defects in LRRK2 create an immune milieu that alters activation of glial cells and may trigger PD.