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

Abstract

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.

The role of the Golgi apparatus in disease (Review)

“…Finally, Golgi alteration may trigger a stress response and, as consequence, result in neuronal death. Furthermore, Golgi fragmentation in neurodegenerative disease alters protein trafficking and production, such as amyloid precursor protein in Alzheimer's disease (35), and sodium-dependent vitamin c transporter 2 in Huntington's disease (36). The causes of Golgi fragmentation in neurodegenerative diseases may be diverse.…”

Oxidative stress, the blood–brain barrier and neurodegenerative diseases: The critical beneficial role of dietary antioxidants

“…e ., SVCT1 and SVCT2) 62 , 80 . Vitamin C has been linked to uptake by its transporters and a dysregulation of this system contributes to neurodegeneration in HD 81 , 82 .…”