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

Maoxue Tang, Guangping Gao, Carlos B. Rueda, Hang Yu, David N. Thibodeaux, Tomoyuki Awano, Kristin M. Engelstad, Maria-Jose Sanchez-Quintero, Hong Yang, Fanghua Li, Huapeng Li, Qin Su, Kara E. Shetler, Lynne Jones, Ryan Seo, Jonathan McConathy, Elizabeth M. Hillman, Jeffrey L. Noebels, Darryl C. De Vivo () and Umrao R. Monani ()
Additional contact information
Maoxue Tang: Columbia University Medical Center
Guangping Gao: University of Massachusetts Medical School
Carlos B. Rueda: Center for Motor Neuron Biology and Disease, Columbia University Medical Center
Hang Yu: Laboratory for Functional Optical Imaging, Mortimer B. Zuckerman Mind Brain Behavior Institute and Kavli Institute for Brain Science, Columbia University
David N. Thibodeaux: Laboratory for Functional Optical Imaging, Mortimer B. Zuckerman Mind Brain Behavior Institute and Kavli Institute for Brain Science, Columbia University
Tomoyuki Awano: Columbia University Medical Center
Kristin M. Engelstad: Colleen Giblin Laboratory, Columbia University Medical Center
Maria-Jose Sanchez-Quintero: Columbia University Medical Center
Hong Yang: Colleen Giblin Laboratory, Columbia University Medical Center
Fanghua Li: Colleen Giblin Laboratory, Columbia University Medical Center
Huapeng Li: University of Massachusetts Medical School
Qin Su: University of Massachusetts Medical School
Kara E. Shetler: Colleen Giblin Laboratory, Columbia University Medical Center
Lynne Jones: Washington University School of Medicine
Ryan Seo: Baylor College of Medicine
Jonathan McConathy: University of Alabama
Elizabeth M. Hillman: Laboratory for Functional Optical Imaging, Mortimer B. Zuckerman Mind Brain Behavior Institute and Kavli Institute for Brain Science, Columbia University
Jeffrey L. Noebels: Baylor College of Medicine
Darryl C. De Vivo: Center for Motor Neuron Biology and Disease, Columbia University Medical Center
Umrao R. Monani: Columbia University Medical Center

Nature Communications, 2017, vol. 8, issue 1, 1-15

Abstract: Abstract 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.

Date: 2017
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DOI: 10.1038/ncomms14152

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