Aims: Huntington's disease (HD) is a neurodegenerative disorder characterized by progressive abnormalities in cognitive function, mental state, and motor control. 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.
Bibliographical noteFunding Information:
We are indebted to T. Valencia and A. Gallastegui-Arrigoni for assistance. This work was supported by Chilean FONDECYT grants 1151206 and 1110571 (MAC), 1141015 (LFB), Chilean CONICYT grants 21110592 (ACP) and 21100320 (FAB), DID-UACh University Research Grant from the Universidad Austral de Chile, Valdivia, Chile (MAC) and International SfA Grant (MAC). MPM, AIA, ACP, and FAB were CONICYT fellows.
Fondo Nacional de Desarrollo CientD?fico y TecnolD?gico, Grant/Award Number: 1110571, 1141015 and 1151206; ComisiD?n Nacional de InvestigaciD?n CientD?fica y TecnolD?gica, Grant/Award Number: 21100320 and 21110592; DID-UACh University Research Grant from the Universidad Austral de Chile, Valdivia, Chile; International SfA Grant
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