The role of microglial LRRK2 kinase in manganese-induced inflammatory neurotoxicity via NLRP3 inflammasome and RAB10-mediated autophagy dysfunction.

ABSTRACT: Chronic manganese (Mn) exposure can lead to manganism, a neurological disorder sharing common symptoms with Parkinson's disease (PD). Studies have shown that Mn can increase the expression and activity of leucine-rich repeat kinase 2 (LRRK2), leading to inflammation and toxicity in microglia. LRRK2 G2019S mutation also elevates LRRK2 kinase activity. Thus, we tested if Mn-increased microglial LRRK2 kinase is responsible for Mn-induced toxicity, and exacerbated by G2019S mutation, using WT and LRRK2 G2019S knock-in mice and BV2 microglia. Mn (30 mg/kg, nostril instillation, daily for 3 weeks) caused motor deficits, cognitive impairments, and dopaminergic dysfunction in WT mice, which were exacerbated in G2019S mice. Mn induced proapoptotic Bax, NLRP3 inflammasome, IL-1β, and TNF-α in the st

SUBMITTER: Pajarillo E 

PROVIDER: S-EPMC10331485 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature