The Human LRRK2 Modulates the Age-Dependent Effects of Developmental Methylmercury Exposure in Caenorhabditis elegans.

Methylmercury (MeHg) neurotoxicity exhibits age-dependent effects with a latent and/or persistent neurotoxic effect on aged animals. Individual susceptibility to MeHg neurotoxicity is governed by both exposure duration and genetic factors that can magnify or mitigate the pathologic processes associated with this exposure. We previously showed the G2019S mutation of leucine-rich repeat kinase 2 (LRRK2) modulates the response of worms to high levels of MeHg, mitigating its effect on neuronal morphology in pre-vesicles in cephalic (CEP) dopaminergic neurons. Here we sought to better understand the long-term effects of MeHg exposure at low levels (100-fold lower than that in our previous report) and the modulatory role of the LRRK2 mutation. Worms exposed to MeHg (10 or 50 nM) at the larval stage (L1 stage) were compared at adult stages (young age: day 1 adult; middle age: day 5 adult; old age: day 10 adult) for the swimming speeds in M9 buffer, moving speeds during locomotion on an OP50-seeded plate, and the numbers of CEP dopaminergic pre-vesicles, vesicular structures originating from the dendrites of CEP for exportation of cellular content. In addition, the expression levels of Caenorhabditis elegans homologs of dopamine transporter (dat-1) and tyrosine hydroxylase (cat-2) were also analyzed at these adult stages. Our data showed that swimming speeds were reduced in wild-type worms at the day 10 adult stage at 50 nM MeHg level; yet, reduced swimming speeds were noted in the G2019S LRRK2 transgenic line upon MeHg exposures as low as 10 nM. Compared to locomotor speeds, swimming speeds appear to be more sensitive to the behavioral effects of developmental MeHg exposures, as the locomotor speeds were largely intact and indistinguishable from controls following MeHg exposures. Furthermore, we showed an age-dependent modulation of dat-1 and cat-2 expressions, which could also be modified by the LRRK2 mutation. Although MeHg exposures did not change the number of pre-vesicles, the LRRK2 mutation was associated with increased numbers of pre-vesicles in aged worms. Our data suggest that the latent behavioral effects of MeHg are sensitized by the G2019S LRRK2 mutation, and the underlying mechanism likely involves age-dependent changes in dopaminergic signaling.