A failure in energy metabolism and antioxidant uptake precede symptoms of Huntington’s disease in mice

Aníbal I. Acuña, Magdalena Esparza, Carlos Kramm, Felipe A. Beltrán, Alejandra V. Parra, Carlos Cepeda, Carlos A. Toro, René L. Vidal, Claudio Hetz, Ilona I. Concha, Sebastián Brauchi, Michael S. Levine and Maite A. Castro ()
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Aníbal I. Acuña: Instituto de Bioquímica y Microbiología, Facultad de Ciencias, Universidad Austral de Chile, Campus Isla Teja s/n
Magdalena Esparza: Instituto de Bioquímica y Microbiología, Facultad de Ciencias, Universidad Austral de Chile, Campus Isla Teja s/n
Carlos Kramm: Instituto de Bioquímica y Microbiología, Facultad de Ciencias, Universidad Austral de Chile, Campus Isla Teja s/n
Felipe A. Beltrán: Instituto de Bioquímica y Microbiología, Facultad de Ciencias, Universidad Austral de Chile, Campus Isla Teja s/n
Alejandra V. Parra: Instituto de Bioquímica y Microbiología, Facultad de Ciencias, Universidad Austral de Chile, Campus Isla Teja s/n
Carlos Cepeda: Intellectual and Developmental Disabilities Research Center, Semel Institute for Neuroscience and Human Behavior, Brain Research Institute, The David Geffen School of Medicine, 760 Westwood Plaza, University of California Los Angeles
Carlos A. Toro: Escuela de Graduados, Facultad de Ciencias, Universidad Austral de Chile, Campus Isla Teja s/n
René L. Vidal: Instituto de Ciencias Biomédicas, Universidad de Chile, Avda, Independencia 1027
Claudio Hetz: Neurounion Biomedical Foundation, Independencia 1027
Ilona I. Concha: Instituto de Bioquímica y Microbiología, Facultad de Ciencias, Universidad Austral de Chile, Campus Isla Teja s/n
Sebastián Brauchi: Centro de Investigación Sur-Austral en Enfermedades del Sistema Nervioso (CISNe), Universidad Austral de Chile, Campus Isla Teja s/n
Michael S. Levine: Intellectual and Developmental Disabilities Research Center, Semel Institute for Neuroscience and Human Behavior, Brain Research Institute, The David Geffen School of Medicine, 760 Westwood Plaza, University of California Los Angeles
Maite A. Castro: Instituto de Bioquímica y Microbiología, Facultad de Ciencias, Universidad Austral de Chile, Campus Isla Teja s/n

Nature Communications, 2013, vol. 4, issue 1, 1-13

Abstract: Abstract Huntington’s disease has been associated with a failure in energy metabolism and oxidative damage. Ascorbic acid is a powerful antioxidant highly concentrated in the brain where it acts as a messenger, modulating neuronal metabolism. Using an electrophysiological approach in R6/2 HD slices, we observe an abnormal ascorbic acid flux from astrocytes to neurons, which is responsible for alterations in neuronal metabolic substrate preferences. Here using striatal neurons derived from knock-in mice expressing mutant huntingtin (STHdhQ cells), we study ascorbic acid transport. When extracellular ascorbic acid concentration increases, as occurs during synaptic activity, ascorbic acid transporter 2 (SVCT2) translocates to the plasma membrane, ensuring optimal ascorbic acid uptake for neurons. In contrast, SVCT2 from cells that mimic HD symptoms (dubbed HD cells) fails to reach the plasma membrane under the same conditions. We reason that an early impairment of ascorbic acid uptake in HD neurons could lead to early metabolic failure promoting neuronal death.

Date: 2013
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DOI: 10.1038/ncomms3917

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