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 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. During synaptic activity, ascorbic acid is released from glial intracellular reservoirs and it is taken up by neurons. Using an electrophysiological approach in YAC128 HD slices, we observe a decreased ascorbic acid flux from astrocytes to neurons, which is responsible for alterations in neuronal metabolic substrate preferences. Ascorbic acid efflux and recycling was decreased in cultured astrocytes from YAC128 HD mice. Our findings were confirmed in experiments using GFAP-HD160Q, a HD mice model expressing mutant N-terminal Huntingtin mainly in astrocytes. We demonstrated that ascorbic acid is released from astrocytes through extracellular vesicles (EV). Decreased number of particles and exosomal markers were observed in EV fractions obtained from cultured YAC128 HD astrocytes, as well as, from Huntingtin KO cells. Using electronic microscopy, we observed a decreased number of multivesicular bodies (MVBs) in the striatum of YAC128 HD mice. This support the idea that MVBs biogenesis is altered in presence of mutant Htt. Therefore, we conclude that a decrease in EV-mediated ascorbic release from astrocytes would be responsible for the early metabolic failure in HD.