Mitochondrial dysfunction underlies conserved roles for LRRK2 in inflammation and pathogen resistance

Robert O Watson Portrait

Mutations in Leucine-rich repeat kinase 2 (LRRK2) have been linked most infamously to Parkinson’s disease but also to a host of chronic inflammatory diseases, cancer, and susceptibility to infection; however, the underlying mechanisms through which LRRK2 mutations promote disease are unknown. We discovered that macrophages harboring the common human mutation Lrrk2G2019S are more prone to regulated cell death in response to both Mycobacterium tuberculosis (Mtb) infection and canonical inflammasome activation. Inflammasome activation alone triggers Lrrk2G2019S mitochondrial hyperpolarization and superoxide overproduction, which increases sensitivity to gasdermin-D pore formation, cytosolic mtDNA release, and ZBP1-dependent PANoptosis. Consistent with enhanced proinflammatory cell death, Lrrk2G2019S mice experience dramatic hyperinflammation during Mtb infection and harbor increased bacterial loads. Remarkably, expression of hLRRK2G2019S in Drosophila melanogaster recapitulates a similar phenotype, whereby LRRK2G2019S-mitochondrial defects promote hyperinflammation and limit clearance of bacterial pathogens. This study highlights a role for inflammasome-mediated cell death in LRRK2 disease phenotypes and suggests that LRRK2’s control of mitochondrial homeostasis is evolutionarily linked to regulating immunity.

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Thursday, August 26, 2021 - 13:00 ET
Robert O. Watson (Texas A&M University)