Altered lactate metabolism in Huntington's disease is dependent on GLUT3 expression

Macarena Solís-Maldonado, María Paz Miró, Aníbal I. Acuña, Adriana Covarrubias-Pinto, Anitsi Loaiza, Gonzalo Mayorga, Felipe A. Beltrán, Carlos Cepeda, Michael S. Levine, Ilona I. Concha, Luis Federico Bátiz, Mónica A. Carrasco, Maite A. Castro

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

HD is characterized by a failure in brain energy metabolism. It has been proposed that monocarboxylates, such as lactate, support brain activity. During neuronal synaptic activity, ascorbic acid released from glial cells stimulates lactate and inhibits glucose transport. The aim of this study was to evaluate the expression and function of monocarboxylate transporters (MCTs) in two HD models. Methods: Using immunofluorescence, qPCR, and Western blot analyses, we explored mRNA and protein levels of MCTs in the striatum of R6/2 animals and HdhQ7/111 cells. We also evaluated MCT function in HdhQ7/111 cells using radioactive tracers and the fluorescent lactate sensor Laconic. Results: We found no significant differences in the mRNA or protein levels of neuronal MCTs. Functional analyses revealed that neuronal MCT2 had a high catalytic efficiency in HD cells. Ascorbic acid did not stimulate lactate uptake in HD cells. Ascorbic acid was also unable to inhibit glucose transport in HD cells because they exhibit decreased expression of the neuronal glucose transporter GLUT3. Conclusion: We demonstrate that stimulation of lactate uptake by ascorbic acid is a consequence of inhibiting glucose transport. Supporting this, lactate transport stimulation by ascorbic acid in HD cells was completely restored by overexpressing GLUT3. Therefore, alterations in GLUT3 expression could be responsible for inefficient use of lactate in HD neurons, contributing to the metabolic failure observed in HD.
Original languageAmerican English
Pages (from-to)343-352
Number of pages10
JournalCNS Neuroscience and Therapeutics
Volume24
Issue number4
DOIs
StatePublished - 1 Apr 2018

Keywords

  • glucose
  • MCT
  • monocarboxylate

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