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 C. 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 paper 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 HRMS-based metabolomics can be used in this model to study environmental and genetic contributors to complex human disease.

High-resolution metabolomics data was generated using samples collected per the methods described in the manuscript. Files generated from the Thermo orbitrap instrument were extracted using the apLCMS and xMSanalyzer R packages.

The raw data in sheet 1 should be treated as follows:

Retain a feature in the feature table if its intensity is 1.5 times that of the average intensity of the feature in the M9 blank sample. Null (intensity = 0) values should be replaced with half the value of the minimum intensity of that feature. 

The biological relevance of the features significantly associated with the genetic or toxicant perturbation can be determined using pathway analysis hosted on MetaboAnalyst.