title: A failure in energy metabolism and antioxidant uptake precede symptoms of Huntington's disease in mice.
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.
authors: 1] Instituto de Bioquímica y Microbiología, Facultad de Ciencias, Universidad Austral de Chile, Campus Isla Teja s/n, Valdivia, 5090000 Chile [2] Centro de Investigación Sur-Austral en Enfermedades del Sistema Nervioso (CISNe), Universidad Austral de Chile, Campus Isla Teja s/n, Valdivia, 5090000 Chile [3] Escuela de Graduados, Facultad de Ciencias, Universidad Austral de Chile, Campus Isla Teja s/n, Valdivia, 5090000 Chile [4].
authors: Aníbal I
authors: AI
authors: Acuña
authors: 1] Instituto de Bioquímica y Microbiología, Facultad de Ciencias, Universidad Austral de Chile, Campus Isla Teja s/n, Valdivia, 5090000 Chile [2] Centro de Investigación Sur-Austral en Enfermedades del Sistema Nervioso (CISNe), Universidad Austral de Chile, Campus Isla Teja s/n, Valdivia, 5090000 Chile [3].
authors: Magdalena
authors: M
authors: Esparza
authors: 1] Instituto de Bioquímica y Microbiología, Facultad de Ciencias, Universidad Austral de Chile, Campus Isla Teja s/n, Valdivia, 5090000 Chile [2] Centro de Investigación Sur-Austral en Enfermedades del Sistema Nervioso (CISNe), Universidad Austral de Chile, Campus Isla Teja s/n, Valdivia, 5090000 Chile [3].
authors: Carlos
authors: C
authors: Kramm
authors: 1] Instituto de Bioquímica y Microbiología, Facultad de Ciencias, Universidad Austral de Chile, Campus Isla Teja s/n, Valdivia, 5090000 Chile [2] Centro de Investigación Sur-Austral en Enfermedades del Sistema Nervioso (CISNe), Universidad Austral de Chile, Campus Isla Teja s/n, Valdivia, 5090000 Chile [3] Escuela de Graduados, Facultad de Ciencias, Universidad Austral de Chile, Campus Isla Teja s/n, Valdivia, 5090000 Chile.
authors: Felipe A
authors: FA
authors: Beltrán
authors: 1] Instituto de Bioquímica y Microbiología, Facultad de Ciencias, Universidad Austral de Chile, Campus Isla Teja s/n, Valdivia, 5090000 Chile [2] Centro de Investigación Sur-Austral en Enfermedades del Sistema Nervioso (CISNe), Universidad Austral de Chile, Campus Isla Teja s/n, Valdivia, 5090000 Chile.
authors: Alejandra V
authors: AV
authors: Parra
authors: 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, Los Angeles, California 90095-1759, USA.
authors: Carlos
authors: C
authors: Cepeda
authors: 1] Escuela de Graduados, Facultad de Ciencias, Universidad Austral de Chile, Campus Isla Teja s/n, Valdivia, 5090000 Chile [2] Instituto de Fisiología, Facultad de Medicina, Universidad Austral de Chile, Campus Isla Teja s/n, Valdivia, 5090000 Chile.
authors: Carlos A
authors: CA
authors: Toro
authors: Instituto de Ciencias Biomédicas, Universidad de Chile, Avda, Independencia 1027, Santiago, Chile.
authors: René L
authors: RL
authors: Vidal
authors: Neurounion Biomedical Foundation, Independencia 1027, Santiago, Chile.
authors: Claudio
authors: C
authors: Hetz
authors: Instituto de Bioquímica y Microbiología, Facultad de Ciencias, Universidad Austral de Chile, Campus Isla Teja s/n, Valdivia, 5090000 Chile.
authors: Ilona I
authors: II
authors: Concha
authors: 1] Centro de Investigación Sur-Austral en Enfermedades del Sistema Nervioso (CISNe), Universidad Austral de Chile, Campus Isla Teja s/n, Valdivia, 5090000 Chile [2] Instituto de Fisiología, Facultad de Medicina, Universidad Austral de Chile, Campus Isla Teja s/n, Valdivia, 5090000 Chile.
authors: Sebastián
authors: S
authors: Brauchi
authors: 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, Los Angeles, California 90095-1759, USA.
authors: Michael S
authors: MS
authors: Levine
authors: 1] Instituto de Bioquímica y Microbiología, Facultad de Ciencias, Universidad Austral de Chile, Campus Isla Teja s/n, Valdivia, 5090000 Chile [2] Centro de Investigación Sur-Austral en Enfermedades del Sistema Nervioso (CISNe), Universidad Austral de Chile, Campus Isla Teja s/n, Valdivia, 5090000 Chile.
authors: Maite A
authors: MA
authors: Castro
mesh_terms: D000818:Animals; D001205:Ascorbic Acid / Q000378:metabolism*; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004734:Energy Metabolism; D005260:Female; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009457:Neuroglia / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D021381:Protein Transport; D017208:Rats, Wistar; D060347:Sodium-Coupled Vitamin C Transporters / Q000235:genetics / Q000378:metabolism
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; C555165:Slc23a2 protein, mouse; D060347:Sodium-Coupled Vitamin C Transporters; D001205:Ascorbic Acid