2. Academic Validation
  3. Brain microvasculature defects and Glut1 deficiency syndrome averted by early repletion of the glucose transporter-1 protein

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

  • Nat Commun. 2017 Jan 20:8:14152. doi: 10.1038/ncomms14152.
Maoxue Tang 1 2,  Guangping Gao 3 4,  Carlos B Rueda 2 5 6,  Hang Yu 7,  David N Thibodeaux 7,  Tomoyuki Awano 1 2,  Kristin M Engelstad 5 6,  Maria-Jose Sanchez-Quintero 6,  Hong Yang 5 6,  Fanghua Li 5 6,  Huapeng Li 3 4,  Qin Su 3 4,  Kara E Shetler 5 6,  Lynne Jones 8,  Ryan Seo 9,  Jonathan McConathy 10,  Elizabeth M Hillman 7,  Jeffrey L Noebels 9,  Darryl C De Vivo 2 5 6,  Umrao R Monani 1 2 6
Affiliations

Affiliations

  • 1 Department of Pathology &Cell Biology, Columbia University Medical Center, New York, New York 10032, USA.
  • 2 Center for Motor Neuron Biology and Disease, Columbia University Medical Center, New York, New York 10032, USA.
  • 3 Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, Massachusetts 010605, USA.
  • 4 Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, Massachusetts 010605, USA.
  • 5 Colleen Giblin Laboratory, Columbia University Medical Center, New York, New York 10032, USA.
  • 6 Department of Neurology, Columbia University Medical Center, New York, New York 10032, USA.
  • 7 Laboratory for Functional Optical Imaging, Departments of Biomedical Engineering and Radiology, Mortimer B. Zuckerman Mind Brain Behavior Institute and Kavli Institute for Brain Science, Columbia University, New York, New York 10027, USA.
  • 8 Department of Radiology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
  • 9 Department of Neurology, Baylor College of Medicine, Houston, Texas 77030, USA.
  • 10 Division of Molecular Imaging and Therapeutics, University of Alabama, Birmingham, Alabama 35249, USA.
PMID: 28106060 DOI: 10.1038/ncomms14152
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.

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