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Methylmercury toxicity: a genetic approach

Abstract

Parkinson's disease (PD) is a progressive, neurodegenerative disorder afflicting ~2% of the US population1. It is characterized by a gradual loss of motor function due to dopaminergic (DAergic) neurodegeneration within the substantia nigra pars compacta (SNpc) and loss of DAergic terminals in the striatum2. Mechanisms underlying the selective DAergic neurodegeneration are poorly understood and there is a dearth of information about the gene-environment interface that sets the stage for this vulnerability. Methylmercury (MeHg) is a potent neurotoxin affecting both the developing and mature central nervous system (CNS), indiscriminately disrupting multiple homeostatic pathways. A causal relationship exists between exposure to MeHg and a number of neurodegenerative diseases, including PD) and considering that MeHg derived from fish consumption, such as in the Brazilian Amazon region, leads to increased prevalence of numerous diseases, that including neurodegenerative disorders, such as PD, and compelling evidence invokes dopaminergic (DAergic) dysfunction in MeHg-induced neurotoxicity with multiple shared effector mechanisms in the etiologies of both disorders. As in other vulnerable populations throughout the world, Amazonian riverine populations in Brazil are chronically exposed to this metal, that can leads to increased prevalence of numerous diseases, including neurodegenerative disorders. The nematode, Caenorhabditis elegans (C. elegans) and mammals share a highly conserved genetic code. Thus, C. elegans is ideally suited for discovering the molecular mechanisms associated with MeHg-induced neurotoxicity within the context of genetic susceptibility. The aim of this study is to test the hypothesis that genetic risk factors modify susceptibility to MeHg-induced DAergic neurotoxicity and neurodegeneration. To address the hypothesis we will perform a genome-wide RNAi-based screen to identify genetic factors and mutations that modify MeHg-induced toxicity in C. elegans, using green fluorescence intensity as a read-out of oxidative stress, a key factor mediating MeHg-induced toxicity. This experimental design will delineate the functional relationships between multiple genetic factors that modify MeHg-induced neurotoxicity in C. elegans and identify genes and mutations that segregate with MeHg-induced disease, thus establish a link between MeHg and genes that hasten susceptibility to neurodegenerative disorders, such as PD. (AU)

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Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
ASCHNER, MICHAEL; SKALNY, ANATOLY V.; MARTINS, AIRTON C.; SINITSKII, ANTON I.; FARINA, MARCELO; LU, RONGZHU; BARBOSA, FERNANDO; GLUHCHEVA, YORDANKA G.; SANTAMARIA, ABEL; TINKOV, ALEXEY A.. Ferroptosis as a mechanism of non-ferrous metal toxicity. ARCHIVES OF TOXICOLOGY, v. N/A, p. 27-pg., . (21/08139-4, 18/24069-3)
SKALNY, ANATOLY, V; ASCHNER, MICHAEL; SEKACHEVA, MARINA, I; SANTAMARIA, ABEL; BARBOSA, FERNANDO; FERRER, BEATRIZ; AASETH, JAN; PAOLIELLO, MONICA M. B.; ROCHA, JOAO B. T.; TINKOV, ALEXEY A.. Mercury and cancer: Where are we now after two decades of research?. Food and Chemical Toxicology, v. 164, p. 11-pg., . (21/08139-4, 18/24069-3)

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