Macarena Solís-Maldonado1,2, María Paz Miró1,2, Aníbal I Acuña1,2, Adriana Covarrubias-Pinto1,2, Anitsi Loaiza1,2, Gonzalo Mayorga1,2, Felipe A Beltrán1,2, Carlos Cepeda3, Michael S Levine3, Ilona I Concha1, Luis Federico Bátiz2,4,5,6, Mónica A Carrasco6,7, Maite A Castro1,2,6. 1. Instituto de Bioquímica y Microbiología, Facultad de Ciencias, Universidad Austral de Chile, Valdivia, Chile. 2. Center for Interdisciplinary Studies on the Nervous System (CISNe), Universidad Austral de Chile, Valdivia, Chile. 3. Intellectual and Developmental Disabilities Research Center, Semel Institute for Neuroscience and Human Behaviour, Brain Research Institute, The David Geffen School of Medicine, UCLA, Los Angeles, CA, USA. 4. Instituto de Anatomía, Histología y Patología, Facultad de Medicina, Universidad Austral de Chile, Valdivia, Chile. 5. Centro de Investigación Biomédica (CIB), Facultad de Medicina, Universidad de Los Andes, Santiago, Chile. 6. Research Initiative for Brain Rejuvenation (ReBrain), Valdivia, Chile. 7. Departamento de Ciencias Básicas Biomédicas, Facultad de Ciencias de la Salud, Universidad de Talca, Talca, Chile.
Abstract
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.
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.
Authors: S Bröer; B Rahman; G Pellegri; L Pellerin; J L Martin; S Verleysdonk; B Hamprecht; P J Magistretti Journal: J Biol Chem Date: 1997-11-28 Impact factor: 5.157
Authors: S E Browne; A C Bowling; U MacGarvey; M J Baik; S C Berger; M M Muqit; E D Bird; M F Beal Journal: Ann Neurol Date: 1997-05 Impact factor: 10.422
Authors: Sebastian Brauchi; Maria C Rauch; Ivan E Alfaro; Christian Cea; Ilona I Concha; Dale J Benos; Juan G Reyes Journal: Am J Physiol Cell Physiol Date: 2004-11-10 Impact factor: 4.249
Authors: 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 Journal: CNS Neurosci Ther Date: 2018-04 Impact factor: 5.243