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Brain microvasculature defects and Glut1 deficiency syndrome averted by early repletion of the glucose transporter-1 protein

Haploinsufficiency of the SLC2A1 gene and paucity of its translated product, the glucose transporter-1 (Glut1) protein, disrupt brain function and cause the neurodevelopmental disorder, Glut1 deficiency syndrome (Glut1 DS). There is little to suggest how reduced Glut1 causes cognitive dysfunction an...

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Autores principales: Tang, Maoxue, Gao, Guangping, Rueda, Carlos B., Yu, Hang, Thibodeaux, David N., Awano, Tomoyuki, Engelstad, Kristin M., Sanchez-Quintero, Maria-Jose, Yang, Hong, Li, Fanghua, Li, Huapeng, Su, Qin, Shetler, Kara E., Jones, Lynne, Seo, Ryan, McConathy, Jonathan, Hillman, Elizabeth M., Noebels, Jeffrey L., De Vivo, Darryl C., Monani, Umrao R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5263887/
https://www.ncbi.nlm.nih.gov/pubmed/28106060
http://dx.doi.org/10.1038/ncomms14152
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author Tang, Maoxue
Gao, Guangping
Rueda, Carlos B.
Yu, Hang
Thibodeaux, David N.
Awano, Tomoyuki
Engelstad, Kristin M.
Sanchez-Quintero, Maria-Jose
Yang, Hong
Li, Fanghua
Li, Huapeng
Su, Qin
Shetler, Kara E.
Jones, Lynne
Seo, Ryan
McConathy, Jonathan
Hillman, Elizabeth M.
Noebels, Jeffrey L.
De Vivo, Darryl C.
Monani, Umrao R.
author_facet Tang, Maoxue
Gao, Guangping
Rueda, Carlos B.
Yu, Hang
Thibodeaux, David N.
Awano, Tomoyuki
Engelstad, Kristin M.
Sanchez-Quintero, Maria-Jose
Yang, Hong
Li, Fanghua
Li, Huapeng
Su, Qin
Shetler, Kara E.
Jones, Lynne
Seo, Ryan
McConathy, Jonathan
Hillman, Elizabeth M.
Noebels, Jeffrey L.
De Vivo, Darryl C.
Monani, Umrao R.
author_sort Tang, Maoxue
collection PubMed
description Haploinsufficiency of the SLC2A1 gene and paucity of its translated product, the glucose transporter-1 (Glut1) protein, disrupt brain function and cause the neurodevelopmental disorder, Glut1 deficiency syndrome (Glut1 DS). There is little to suggest how reduced Glut1 causes cognitive dysfunction and no optimal treatment for Glut1 DS. We used model mice to demonstrate that low Glut1 protein arrests cerebral angiogenesis, resulting in a profound diminution of the brain microvasculature without compromising the blood–brain barrier. Studies to define the temporal requirements for Glut1 reveal that pre-symptomatic, AAV9-mediated repletion of the protein averts brain microvasculature defects and prevents disease, whereas augmenting the protein late, during adulthood, is devoid of benefit. Still, treatment following symptom onset can be effective; Glut1 repletion in early-symptomatic mutants that have experienced sustained periods of low brain glucose nevertheless restores the cerebral microvasculature and ameliorates disease. Timely Glut1 repletion may thus constitute an effective treatment for Glut1 DS.
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spelling pubmed-52638872017-02-03 Brain microvasculature defects and Glut1 deficiency syndrome averted by early repletion of the glucose transporter-1 protein Tang, Maoxue Gao, Guangping Rueda, Carlos B. Yu, Hang Thibodeaux, David N. Awano, Tomoyuki Engelstad, Kristin M. Sanchez-Quintero, Maria-Jose Yang, Hong Li, Fanghua Li, Huapeng Su, Qin Shetler, Kara E. Jones, Lynne Seo, Ryan McConathy, Jonathan Hillman, Elizabeth M. Noebels, Jeffrey L. De Vivo, Darryl C. Monani, Umrao R. Nat Commun Article Haploinsufficiency of the SLC2A1 gene and paucity of its translated product, the glucose transporter-1 (Glut1) protein, disrupt brain function and cause the neurodevelopmental disorder, Glut1 deficiency syndrome (Glut1 DS). There is little to suggest how reduced Glut1 causes cognitive dysfunction and no optimal treatment for Glut1 DS. We used model mice to demonstrate that low Glut1 protein arrests cerebral angiogenesis, resulting in a profound diminution of the brain microvasculature without compromising the blood–brain barrier. Studies to define the temporal requirements for Glut1 reveal that pre-symptomatic, AAV9-mediated repletion of the protein averts brain microvasculature defects and prevents disease, whereas augmenting the protein late, during adulthood, is devoid of benefit. Still, treatment following symptom onset can be effective; Glut1 repletion in early-symptomatic mutants that have experienced sustained periods of low brain glucose nevertheless restores the cerebral microvasculature and ameliorates disease. Timely Glut1 repletion may thus constitute an effective treatment for Glut1 DS. Nature Publishing Group 2017-01-20 /pmc/articles/PMC5263887/ /pubmed/28106060 http://dx.doi.org/10.1038/ncomms14152 Text en Copyright © 2017, The Author(s) http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Tang, Maoxue
Gao, Guangping
Rueda, Carlos B.
Yu, Hang
Thibodeaux, David N.
Awano, Tomoyuki
Engelstad, Kristin M.
Sanchez-Quintero, Maria-Jose
Yang, Hong
Li, Fanghua
Li, Huapeng
Su, Qin
Shetler, Kara E.
Jones, Lynne
Seo, Ryan
McConathy, Jonathan
Hillman, Elizabeth M.
Noebels, Jeffrey L.
De Vivo, Darryl C.
Monani, Umrao R.
Brain microvasculature defects and Glut1 deficiency syndrome averted by early repletion of the glucose transporter-1 protein
title Brain microvasculature defects and Glut1 deficiency syndrome averted by early repletion of the glucose transporter-1 protein
title_full Brain microvasculature defects and Glut1 deficiency syndrome averted by early repletion of the glucose transporter-1 protein
title_fullStr Brain microvasculature defects and Glut1 deficiency syndrome averted by early repletion of the glucose transporter-1 protein
title_full_unstemmed Brain microvasculature defects and Glut1 deficiency syndrome averted by early repletion of the glucose transporter-1 protein
title_short Brain microvasculature defects and Glut1 deficiency syndrome averted by early repletion of the glucose transporter-1 protein
title_sort brain microvasculature defects and glut1 deficiency syndrome averted by early repletion of the glucose transporter-1 protein
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5263887/
https://www.ncbi.nlm.nih.gov/pubmed/28106060
http://dx.doi.org/10.1038/ncomms14152
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