Impaired intracellular trafficking of sodium‐dependent vitamin C transporter 2 contributes to the redox imbalance in Huntington’s disease

• Published in: Journal of neuroscience research Vol. 99; no. 1; pp. 223 - 235
• Main Authors: Covarrubias‐Pinto, Adriana, Parra, Alejandra V., Mayorga‐Weber, Gonzalo, Papic, Eduardo, Vicencio, Isidora, Ehrenfeld, Pamela, Rivera, Francisco J., Castro, Maite A.
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.01.2021
• Subjects: Acids; Animal models; Antioxidants; Ascorbic acid; Brain damage; Calcium; Calcium signalling; Endosomes; Energy metabolism; Glutamine; Golgi apparatus; Huntingtin; Huntington's disease; Huntingtons disease; Localization; Membrane trafficking; Membranes; Metabolism; neurodegeneration; Neurodegenerative diseases; neuron‐glia interaction; Organelles; Oxidative metabolism; Proteins; Sodium; Translocation; Transport buildings, stations and terminals; Vitamin C; neurodegeneration; ascorbic acid; neuron-glia interaction; vitamin C
• ISSN: 0360-4012; 1097-4547
• DOI: 10.1002/jnr.24693

Huntington's disease (HD) is a neurodegenerative disorder caused by a glutamine expansion at the first exon of the huntingtin gene. Huntingtin protein (Htt) is ubiquitously expressed and it is localized in several organelles, including endosomes. HD is 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. It is transported into neurons via the sodium‐dependent vitamin C transporter 2 (SVCT2). During synaptic activity, ascorbic acid is released from glial reservoirs to the extracellular space, inducing an increase in SVCT2 localization at the plasma membrane. Here, we studied SVCT2 trafficking and localization in HD. SVCT2 is decreased at synaptic terminals in YAC128 male mice. Using cellular models for HD (STHdhQ7 and STHdhQ111 cells), we determined that SVCT2 trafficking through secretory and endosomal pathways is altered in resting conditions. We observed Golgi fragmentation and SVCT2/Htt‐associated protein‐1 mis‐colocalization. Additionally, we observed altered ascorbic acid‐induced calcium signaling that explains the reduced SVCT2 translocation to the plasma membrane in the presence of extracellular ascorbic acid (active conditions) described in our previous results. Therefore, SVCT2 trafficking to the plasma membrane is altered in resting and active conditions in HD, explaining the redox imbalance observed during early stages of the disease. Extracellular ascorbic acid induces Ca2+ influx, stimulating sodium‐dependent vitamin C transporter 2 (SVCT2) anterograde trafficking in wild‐type cells. No ascorbic acid‐induced cytosolic Ca2+ increase was observed in Huntington's disease (HD) cells. Thus, SVCT2 would fail to reach the cellular surface, affecting ascorbic acid uptake in HD cells.