Distinct roles of ascorbic acid in extracellular vesicles and free form: Implications for metabolism and oxidative stress in presymptomatic Huntington's disease: Ascorbic acid in early Huntington's disease
Por:
Beltrán F.A., Torres-Díaz L. L., Troncoso-Escudero P., Villalobos-González J., Mayorga-Weber G., Lara M., Covarrubias-Pinto A., Valdivia S., Vicencio I., Papic E., Paredes-Martínez C., Silva-Januàrio M.E., Rojas A., daSilva L.L.P., Court F., Rosas-Arellano A., Bátiz L.F., Rojas P., Rivera F.J., Castro M.A.
Publicada:
1 ene 2025
Ahead of Print:
1 dic 2024
Resumen:
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. © 2024 The Authors
Filiaciones:
Beltrán F.A.:
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, Frankfurt am Main, 60590, 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 M.E.:
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 L.L.P.:
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, United States
Rosas-Arellano A.:
Unidad de Imagenología, Instituto de Fisiología Celular, UNAM, CDMX, Mexico
Bátiz L.F.:
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 F.J.:
Translational Regenerative Neurobiology Group (TReN), Molecular and Integrative Biosciences Research Program (MIBS), Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, Finland
Castro M.A.:
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, United States
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