The Role of Human LRRK2 in Methylmercury-Induced Inhibition of Microvesicle Formation of Cephalic Neurons in Caenorhabdi
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ORIGINAL ARTICLE
The Role of Human LRRK2 in Methylmercury-Induced Inhibition of Microvesicle Formation of Cephalic Neurons in Caenorhabditis elegans Tao Ke 1 & Abel Santamaria 2 & Joao B. T. Rocha 3 & Alexey A. Tinkov 4,5 & Rongzhu Lu 6 & Aaron B. Bowman 7 & Michael Aschner 1,5 Received: 13 June 2020 / Revised: 21 July 2020 / Accepted: 22 July 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract In a previous study, we have shown that methylmercury (MeHg) exposure causes focal aggregation of intracellular transgenic mCherry protein in dendrites of cephalic (CEP) neurons in Caenorhabditis elegans (C. elegans). However, the underlying mechanism is unknown. We hypothesized that reduced cellular release of mCherry via extracellular vesicles by MeHg contributes to its accumulation and intracellular aggregation. Thus, we characterized vesicular structures in CEP dendrites, which were 1–3 μm in diameter and could readily bud off from the plasma membrane of the dendrites. Chronic treatment of C. elegans with MeHg (5 μM, 4–10 days) reduced the number of vesicles attached to CEP dendrites (attached vesicles) and vesicles unattached to CEP dendrites (unattached vesicles), as well as the presence of extracellular mCherry, supporting the hypothesis that release of mCherry by microvesicle formation is inhibited by MeHg. Leucine-rich repeat kinase 2 (LRRK2) has an important function in membrane biology. Further investigation showed that the effects of MeHg were modified by human LRRK2. In worms with the wild-type LRRK2, the vesicle numbers were significantly reduced by MeHg (0.5 and 5 μM). The effects of MeHg on the presence of extracellular mCherry and attached vesicles were modified by the human wild-type LRRK2. Independent of MeHg treatment, the G2019S mutant LRRK2 showed reduced number of unattached vesicles; however, the levels of extracellular mCherry were increased. Knockdown of C. elegans irk-1, the homolog of human LRRK2, reduced the number of attached vesicles, corroborating that LRRK2 plays an important role in the formation of microvesicles. Keywords Methylmercury . Leucine-rich repeat kinase 2 . CEP neuron . Microvesicle
* Michael Aschner [email protected] 1
Department of Molecular Pharmacology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Forchheimer Building, Room 209, Bronx, NY 10461, USA
2
Laboratorio de Aminoácidos Excitadores, Instituto Nacional de Neurología y Neurocirugía, 14269 Mexico City, Mexico
3
Department of Biochemistry and Molecular Biology, Federal University of Santa Maria, Santa Maria, RS, Brazil
4
Yaroslavl State University, Sovetskaya St., 14, Yaroslavl, Russia 150000
5
IM Sechenov First Moscow State Medical University, Sechenov University, Moscow, Russia
6
Department of Preventive Medicine and Public Health Laboratory Sciences, School of Medicine, Jiangsu University, Zhenjiang 212013, Jiangsu, China
7
School of Health Sciences, Purdue University, West Lafayette, IN 47907-2051, USA
Introduction In a previous study of Ca
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