PMID- 33538833
OWN - NLM
STAT- MEDLINE
DCOM- 20210818
LR  - 20240402
IS  - 1096-0929 (Electronic)
IS  - 1096-6080 (Print)
IS  - 1096-0929 (Linking)
VI  - 180
IP  - 2
DP  - 2021 Apr 12
TI  - Genetic or Toxicant-Induced Disruption of Vesicular Monoamine Storage and Global 
      Metabolic Profiling in Caenorhabditis elegans.
PG  - 313-324
LID - 10.1093/toxsci/kfab011 [doi]
AB  - 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.
CI  - (c) 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.
FAU - Bradner, Joshua M
AU  - Bradner JM
AD  - Department of Environmental Health Sciences, Mailman School of Public Health, 
      Columbia University, New York, New York 10032, USA.
FAU - Kalia, Vrinda
AU  - Kalia V
AD  - Department of Environmental Health Sciences, Mailman School of Public Health, 
      Columbia University, New York, New York 10032, USA.
FAU - Lau, Fion K
AU  - Lau FK
AD  - Department of Environmental Health Sciences, Mailman School of Public Health, 
      Columbia University, New York, New York 10032, USA.
FAU - Sharma, Monica
AU  - Sharma M
AD  - Department of Environmental Health Sciences, Mailman School of Public Health, 
      Columbia University, New York, New York 10032, USA.
FAU - Bucher, Meghan L
AU  - Bucher ML
AD  - Department of Environmental Health Sciences, Mailman School of Public Health, 
      Columbia University, New York, New York 10032, USA.
FAU - Johnson, Michelle
AU  - Johnson M
AD  - Department of Environmental Health, Rollins School of Public Health, Emory 
      University, Atlanta, Georgia 30322, USA.
FAU - Chen, Merry
AU  - Chen M
AD  - Department of Environmental Health, Rollins School of Public Health, Emory 
      University, Atlanta, Georgia 30322, USA.
FAU - Walker, Douglas I
AU  - Walker DI
AD  - Department of Environmental Medicine and Public Health, Icahn School of Medicine 
      at Mount Sinai, New York, New York 10029, USA.
FAU - Jones, Dean P
AU  - Jones DP
AD  - Department of Medicine, School of Medicine, Emory University, Atlanta, Georgia 
      30303, USA.
FAU - Miller, Gary W
AU  - Miller GW
AD  - Department of Environmental Health Sciences, Mailman School of Public Health, 
      Columbia University, New York, New York 10032, USA.
LA  - eng
GR  - P30 ES009089/ES/NIEHS NIH HHS/United States
GR  - P30 ES019776/ES/NIEHS NIH HHS/United States
GR  - R01 ES023839/ES/NIEHS NIH HHS/United States
GR  - T32 ES007322/ES/NIEHS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PL  - United States
TA  - Toxicol Sci
JT  - Toxicological sciences : an official journal of the Society of Toxicology
JID - 9805461
RN  - 0 (Membrane Glycoproteins)
RN  - 0 (Vesicular Biogenic Amine Transport Proteins)
RN  - 0 (Vesicular Monoamine Transport Proteins)
SB  - IM
MH  - Animals
MH  - *Caenorhabditis elegans/genetics/metabolism
MH  - Dopaminergic Neurons/metabolism
MH  - Humans
MH  - *Membrane Glycoproteins/metabolism
MH  - Metabolomics
MH  - Mice
MH  - Vesicular Biogenic Amine Transport Proteins
MH  - Vesicular Monoamine Transport Proteins/genetics
PMC - PMC8041460
OTO - NOTNLM
OT  - MPP+
OT  - VMAT
OT  - cat-1
OT  - high-resolution mass spectrometry
OT  - metabolomics
OT  - monoamine
OT  - neurodegeneration
OT  - vesicle
EDAT- 2021/02/05 06:00
MHDA- 2021/08/19 06:00
PMCR- 2022/02/04
CRDT- 2021/02/04 12:14
PHST- 2021/02/05 06:00 [pubmed]
PHST- 2021/08/19 06:00 [medline]
PHST- 2021/02/04 12:14 [entrez]
PHST- 2022/02/04 00:00 [pmc-release]
AID - 6128531 [pii]
AID - kfab011 [pii]
AID - 10.1093/toxsci/kfab011 [doi]
PST - ppublish
SO  - Toxicol Sci. 2021 Apr 12;180(2):313-324. doi: 10.1093/toxsci/kfab011.