Department of Molecular Pharmacology, Albert Einstein College of Medicine, Room 209, Forchheimer Building, 1300 Morris Park Avenue, Bronx, NY, 10461, USA.
IM Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia.
Neurotox Res. 2022 Oct;40(5):1235-1247. doi: 10.1007/s12640-022-00547-x. Epub 2022 Jul 15.
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.
甲基汞（MeHg）的神经毒性具有年龄依赖性，对老年动物具有潜在和/或持久性的神经毒性作用。个体对 MeHg 神经毒性的易感性受暴露持续时间和遗传因素的影响，这些因素可以放大或减轻与这种暴露相关的病理过程。我们之前曾表明，富含亮氨酸重复激酶 2（LRRK2）的 G2019S 突变调节蠕虫对高水平 MeHg 的反应，减轻其对头部（CEP）多巴胺能神经元前囊泡中神经元形态的影响。在这里，我们试图更好地了解低水平 MeHg 暴露（比我们之前报告的水平低 100 倍）的长期影响以及 LRRK2 突变的调节作用。在幼虫阶段（L1 阶段）暴露于 MeHg（10 或 50 nM）的蠕虫在成虫阶段（年轻：成虫第 1 天；中年：成虫第 5 天；老年：成虫第 10 天）进行比较，以评估 M9 缓冲液中的游泳速度、在 OP50 接种板上运动时的运动速度以及 CEP 多巴胺能前囊泡的数量，这些囊泡结构源自 CEP 的树突，用于细胞内容物的输出。此外，还在这些成虫阶段分析了秀丽隐杆线虫多巴胺转运体（dat-1）和酪氨酸羟化酶（cat-2）同源物的表达水平。我们的数据表明，在 50 nM MeHg 水平下，野生型蠕虫在成虫第 10 天的游泳速度降低；然而，在 G2019S LRRK2 转基因系中，甚至在低至 10 nM 的 MeHg 暴露下，游泳速度也降低了。与运动速度相比，游泳速度似乎对发育中的 MeHg 暴露的行为影响更为敏感，因为运动速度在 MeHg 暴露后基本保持完整，与对照无区别。此外，我们还显示了 dat-1 和 cat-2 表达的年龄依赖性调节，该调节也可以被 LRRK2 突变所修饰。尽管 MeHg 暴露并未改变前囊泡的数量，但 LRRK2 突变与老年蠕虫中前囊泡数量的增加有关。我们的数据表明，MeHg 的潜在行为效应被 G2019S LRRK2 突变所敏感化，其潜在机制可能涉及多巴胺能信号的年龄依赖性变化。
