Distinct roles of ascorbic acid in extracellular vesicles and free form: Implications for metabolism and oxidative stress in presymptomatic Huntington's disease.

Autor: Beltrán FA; Instituto de Bioquímica y Microbiología, UACh, Valdivia, Chile; Center for Interdisciplinary Studies on Nervous System (CISNe), UACh, Valdivia, Chile., Torres-Díaz L L; Instituto de Bioquímica y Microbiología, UACh, Valdivia, Chile; Center for Interdisciplinary Studies on Nervous System (CISNe), UACh, Valdivia, Chile; Departamento de Ciencias y Geografía, Facultad de Ciencias Naturales y Exactas, Universidad de Playa Ancha, Valparaíso, Chile., Troncoso-Escudero P; Instituto de Bioquímica y Microbiología, UACh, Valdivia, Chile; Center for Interdisciplinary Studies on Nervous System (CISNe), UACh, Valdivia, Chile., Villalobos-González J; Instituto de Bioquímica y Microbiología, UACh, Valdivia, Chile; Center for Interdisciplinary Studies on Nervous System (CISNe), UACh, Valdivia, Chile., Mayorga-Weber G; Instituto de Bioquímica y Microbiología, UACh, Valdivia, Chile; Center for Interdisciplinary Studies on Nervous System (CISNe), UACh, Valdivia, Chile., Lara M; Departamento de Biología, Universidad de Santiago de Chile, Santiago, Chile., Covarrubias-Pinto A; Instituto de Bioquímica y Microbiología, UACh, Valdivia, Chile; Center for Interdisciplinary Studies on Nervous System (CISNe), UACh, Valdivia, Chile; Institute of Biochemistry II, Goethe University School of Medicine, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany., Valdivia S; Instituto de Bioquímica y Microbiología, UACh, Valdivia, Chile; Center for Interdisciplinary Studies on Nervous System (CISNe), UACh, Valdivia, Chile; Department of Biological and Chemical Sciences, Faculty of Medicine and Sciences, San Sebastián University, Tres Pascualas Campus, Concepción, Chile., Vicencio I; Instituto de Bioquímica y Microbiología, UACh, Valdivia, Chile; Center for Interdisciplinary Studies on Nervous System (CISNe), UACh, Valdivia, Chile., Papic E; Instituto de Bioquímica y Microbiología, UACh, Valdivia, Chile; Center for Interdisciplinary Studies on Nervous System (CISNe), UACh, Valdivia, Chile., Paredes-Martínez C; Instituto de Bioquímica y Microbiología, UACh, Valdivia, Chile; Center for Interdisciplinary Studies on Nervous System (CISNe), UACh, Valdivia, Chile., Silva-Januàrio ME; Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brazil., Rojas A; Center for Interdisciplinary Studies on Nervous System (CISNe), UACh, Valdivia, Chile; Instituto de Medicina, UACh, Valdivia, Chile., daSilva LLP; Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brazil., Court F; Center for Integrative Biology, Universidad Mayor, Santiago, Chile; Geroscience Center for Brain Health and Metabolism (GERO), Santiago, Chile; Buck Institute for Research on Aging, Novato, CA, USA., Rosas-Arellano A; Unidad de Imagenología, Instituto de Fisiología Celular, UNAM, CDMX, Mexico., Bátiz LF; Centro de Investigación e Innovación Biomédica (CIIB), Universidad de Los Andes, Santiago, Chile; Escuela de Medicina, Facultad de Medicina, Universidad de los Andes, Santiago, Chile., Rojas P; Departamento de Biología, Universidad de Santiago de Chile, Santiago, Chile., Rivera FJ; Translational Regenerative Neurobiology Group (TReN), Molecular and Integrative Biosciences Research Program (MIBS), Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, Finland. Electronic address: francisco.rivera@helsinki.fi., Castro MA; Instituto de Bioquímica y Microbiología, UACh, Valdivia, Chile; Center for Interdisciplinary Studies on Nervous System (CISNe), UACh, Valdivia, Chile; Janelia Research Campus HHMI, Ashburn, VA, USA. Electronic address: macastro@uach.cl.
Jazyk: angličtina
Zdroj: Free radical biology & medicine [Free Radic Biol Med] 2024 Dec 09; Vol. 227, pp. 521-535. Date of Electronic Publication: 2024 Dec 09.
DOI: 10.1016/j.freeradbiomed.2024.12.001
Abstrakt: Huntington's disease (HD) is a neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the first exon of the huntingtin gene. The huntingtin protein (Htt) is ubiquitously expressed and localized in several organelles, including endosomes, where it plays an essential role in intracellular trafficking. Presymptomatic HD is associated with a failure in energy metabolism and oxidative stress. Ascorbic acid is a potent antioxidant that plays a key role in modulating neuronal metabolism and is highly concentrated in the brain. During synaptic activity, neurons take up ascorbic acid released by glial cells; however, this process is disrupted in HD. In this study, we aim to elucidate the molecular and cellular mechanisms underlying this dysfunction. Using an electrophysiological approach in presymptomatic YAC128 HD slices, we observed decreased ascorbic acid flux from astrocytes to neurons, which altered neuronal metabolic substrate preferences. Ascorbic acid efflux and recycling were also decreased in cultured astrocytes from YAC128 HD mice. We confirmed our findings using GFAP-HD160Q, an HD mice model expressing mutant N-terminal Htt mainly in astrocytes. For the first time, we demonstrated that ascorbic acid is released from astrocytes via extracellular vesicles (EVs). Decreased number of particles and exosomal markers were observed in EV fractions from cultured YAC128 HD astrocytes and Htt-KD cells. We observed reduced number of multivesicular bodies (MVBs) in YAC128 HD striatum via electron microscopy, suggesting mutant Htt alters MVB biogenesis. EVs containing ascorbic acid effectively reduced reactive oxygen species, whereas "free" ascorbic acid played a role in modulating neuronal metabolic substrate preferences. These findings suggest that the early redox imbalance observed in HD arises from a reduced release of ascorbic acid-containing EVs by astrocytes. Meanwhile, a decrease in "free" ascorbic acid likely contributes to presymptomatic metabolic impairment.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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