Genetic or Toxicant-Induced Disruption of Vesicular Monoamine Storage and Global Metabolic Profiling in Caenorhabditis elegans
Autor: | Merry Chen, Monica Sharma, Fion K Lau, Dean P. Jones, Gary W. Miller, Michelle A. Johnson, Douglas I. Walker, Vrinda Kalia, Meghan L Bucher, Joshua M. Bradner |
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Rok vydání: | 2021 |
Předmět: |
0301 basic medicine
Neurotoxicology Vesicular Monoamine Transport Proteins Toxicology Vesicular monoamine transporter 2 03 medical and health sciences Mice 0302 clinical medicine Dopamine Vesicular Biogenic Amine Transport Proteins medicine Animals Humans Metabolomics Caenorhabditis elegans Membrane Glycoproteins biology Chemistry Dopaminergic Neurons biology.organism_classification Cell biology Vesicular monoamine transporter 030104 developmental biology Monoamine neurotransmitter Catecholamine biology.protein Monoamine transport 030217 neurology & neurosurgery medicine.drug |
Zdroj: | Toxicol Sci |
ISSN: | 1096-0929 |
Popis: | 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. |
Databáze: | OpenAIRE |
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