Genetic or Toxicant-Induced Disruption of Vesicular Monoamine Storage and Global Metabolic Profiling in Caenorhabditis elegans.

Autor:	Bradner JM; Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, New York 10032, USA., Kalia V; Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, New York 10032, USA., Lau FK; Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, New York 10032, USA., Sharma M; Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, New York 10032, USA., Bucher ML; Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, New York 10032, USA., Johnson M; Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, Georgia 30322, USA., Chen M; Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, Georgia 30322, USA., Walker DI; Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA., Jones DP; Department of Medicine, School of Medicine, Emory University, Atlanta, Georgia 30303, USA., Miller GW; Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, New York 10032, USA.
Jazyk:	angličtina
Zdroj:	Toxicological sciences : an official journal of the Society of Toxicology [Toxicol Sci] 2021 Apr 12; Vol. 180 (2), pp. 313-324.
DOI:	10.1093/toxsci/kfab011
Abstrakt:	The proper storage and release of monoamines contributes to a wide range of neuronal activity. Here, we examine the effects of altered vesicular monoamine transport in the nematode Caenorhabditis elegans. The gene cat-1 is responsible for the encoding of the vesicular monoamine transporter (VMAT) in C. elegans and is analogous to the mammalian vesicular monoamine transporter 2 (VMAT2). Our laboratory has previously shown that reduced VMAT2 activity confers vulnerability on catecholamine neurons in mice. The purpose of this article was to determine whether this function is conserved and to determine the impact of reduced VMAT activity in C. elegans. Here we show that deletion of cat-1/VMAT increases sensitivity to the neurotoxicant 1-methyl-4-phenylpyridinium (MPP+) as measured by enhanced degeneration of dopamine neurons. Reduced cat-1/VMAT also induces changes in dopamine-mediated behaviors. High-resolution mass spectrometry-based metabolomics in the whole organism reveals changes in amino acid metabolism, including tyrosine metabolism in the cat-1/VMAT mutants. Treatment with MPP+ disrupted tryptophan metabolism. Both conditions altered glycerophospholipid metabolism, suggesting a convergent pathway of neuronal dysfunction. Our results demonstrate the evolutionarily conserved nature of monoamine function in C. elegans and further suggest that high-resolution mass spectrometry-based metabolomics can be used in this model to study environmental and genetic contributors to complex human disease. (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
Databáze:	MEDLINE
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