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

• Published in: Nature communications Vol. 4; no. 1; p. 2917
• Main Authors: Acuña, Aníbal I., Esparza, Magdalena, Kramm, Carlos, Beltrán, Felipe A., Parra, Alejandra V., Cepeda, Carlos, Toro, Carlos A., Vidal, René L., Hetz, Claudio, Concha, Ilona I., Brauchi, Sebastián, Levine, Michael S., Castro, Maite A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 13.12.2013; Nature Publishing Group; Nature Pub. Group
• Subjects: 13/1; 13/51; 14/1; 14/19; 14/35; 14/63; 42/109; 42/35; 59; 631/378/1689/1558; 631/443/319; 631/80/313; 64; 64/110; 64/60; 692/420; 82; 82/29; 9/74; Animals; Ascorbic Acid - metabolism; Astrocytes - metabolism; Astrocytes - pathology; Cell Line; Cell Membrane - genetics; Cell Membrane - metabolism; Disease Models, Animal; Energy Metabolism; Female; Humanities and Social Sciences; Huntingtin Protein; Huntington Disease - genetics; Huntington Disease - metabolism; Huntington Disease - pathology; Male; Mice; Mice, Transgenic; multidisciplinary; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neuroglia - metabolism; Neuroglia - pathology; Neurons - metabolism; Neurons - pathology; Protein Transport; Rats, Wistar; Science; Science (multidisciplinary); Sodium-Coupled Vitamin C Transporters - genetics; Sodium-Coupled Vitamin C Transporters - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms3917

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. Defective ascorbic acid flux is a sign of metabolic failure associated with Huntington’s disease. Here, Acuña et al. show that reduction in ascorbic acid flux from astrocytes precedes the symptoms of Huntington’s disease in mice and impairs ascorbic acid uptake in neurons.