The Parkinson's disease-associated variant Lrrk2 G2019S confers hyper-susceptibility to inflammasome-mediated cell death and Mycobacterium tuberculosis pathogenesis Conference Paper uri icon


  • Abstract Leucine-rich repeat kinase 2 (LRRK2), a multifunctional kinase linked to Parkinsons disease (PD), has been repeatedly implicated in mycobacterial infection, although its function outside the nervous system is poorly understood. To create a replicative niche within the harsh environment of a macrophage, Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), needs to manipulate two major innate immune pathways, the type I IFN response and regulated cell death (RCD). Previously, we found that loss of LRRK2 (Lrrk2/) in macrophages results in type I IFN defects during Mtb infection in vitro and in vivo. We mechanistically linked this type I IFN reprogramming to LRRK2-dependent mitochondrial dysfunction and leakage of mtDNA into the macrophage cytosol. To further investigate the role of LRRK2 in Mtb pathogenesis, we shifted focus to the G2019S variant of LRRK2, which is the greatest genetic risk factor for PD. While the type I IFN response is normal in Lrrk2G2019S macrophages, their mitochondrial network is fragmented and depolarized. These macrophages also are more prone to a pyroptotic form of regulated cell death (RCD) that is dependent on mtDNA. Importantly, during Mtb infection in vivo, Lrrk2G2019S mice experience hyperinflammation and elevated signatures of pyroptotic cell death. Collectively, these data suggest that Lrrk2G2019S impairs mitochondrial health and enhances inflammatory cell death (pyroptosis) with severe in vivo consequences during Mtb infection. The potent enhanced inflammatory response present in the periphery of G2019S mice in vivo might begin to suggest a model where increased inflammation in the periphery could trigger or exacerbate neurodegeneration in carriers of this allele.

published proceedings


author list (cited authors)

  • Weindel, C. G., Vail, K., Bell, S., Martinez, E., Patrick, K., & Watson, R. O.

citation count

  • 0

complete list of authors

  • Weindel, Chi Gidley||Vail, Krystal||Bell, Samantha||Martinez, Eduardo||Patrick, Kristin||Watson, Robert Owen

publication date

  • May 2021