title: Brain microvasculature defects and Glut1 deficiency syndrome averted by early repletion of the glucose transporter-1 protein.
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.
authors.affiliation: Department of Pathology &Cell Biology, Columbia University Medical Center, New York, New York 10032, USA.|Center for Motor Neuron Biology and Disease, Columbia University Medical Center, New York, New York 10032, USA.
authors.forename: Maoxue
authors.initials: M
authors.lastname: Tang
authors.affiliation: Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, Massachusetts 010605, USA.|Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, Massachusetts 010605, USA.
authors.forename: Guangping
authors.initials: G
authors.lastname: Gao
authors.affiliation: Center for Motor Neuron Biology and Disease, Columbia University Medical Center, New York, New York 10032, USA.|Colleen Giblin Laboratory, Columbia University Medical Center, New York, New York 10032, USA.|Department of Neurology, Columbia University Medical Center, New York, New York 10032, USA.
authors.forename: Carlos B
authors.initials: CB
authors.lastname: Rueda
authors.affiliation: 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.
authors.forename: Hang
authors.identifier: 0000-0003-2923-7872
authors.initials: H
authors.lastname: Yu
authors.affiliation: 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.
authors.forename: David N
authors.initials: DN
authors.lastname: Thibodeaux
authors.affiliation: Department of Pathology &Cell Biology, Columbia University Medical Center, New York, New York 10032, USA.|Center for Motor Neuron Biology and Disease, Columbia University Medical Center, New York, New York 10032, USA.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Awano
authors.affiliation: Colleen Giblin Laboratory, Columbia University Medical Center, New York, New York 10032, USA.|Department of Neurology, Columbia University Medical Center, New York, New York 10032, USA.
authors.forename: Kristin M
authors.initials: KM
authors.lastname: Engelstad
authors.affiliation: Department of Neurology, Columbia University Medical Center, New York, New York 10032, USA.
authors.forename: Maria-Jose
authors.initials: MJ
authors.lastname: Sanchez-Quintero
authors.affiliation: Colleen Giblin Laboratory, Columbia University Medical Center, New York, New York 10032, USA.|Department of Neurology, Columbia University Medical Center, New York, New York 10032, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Yang
authors.affiliation: Colleen Giblin Laboratory, Columbia University Medical Center, New York, New York 10032, USA.|Department of Neurology, Columbia University Medical Center, New York, New York 10032, USA.
authors.forename: Fanghua
authors.initials: F
authors.lastname: Li
authors.affiliation: Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, Massachusetts 010605, USA.|Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, Massachusetts 010605, USA.
authors.forename: Huapeng
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, Massachusetts 010605, USA.|Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, Massachusetts 010605, USA.
authors.forename: Qin
authors.initials: Q
authors.lastname: Su
authors.affiliation: Colleen Giblin Laboratory, Columbia University Medical Center, New York, New York 10032, USA.|Department of Neurology, Columbia University Medical Center, New York, New York 10032, USA.
authors.forename: Kara E
authors.initials: KE
authors.lastname: Shetler
authors.affiliation: Department of Radiology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
authors.forename: Lynne
authors.initials: L
authors.lastname: Jones
authors.affiliation: Department of Neurology, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Ryan
authors.initials: R
authors.lastname: Seo
authors.affiliation: Division of Molecular Imaging and Therapeutics, University of Alabama, Birmingham, Alabama 35249, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: McConathy
authors.affiliation: 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.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Hillman
authors.affiliation: Department of Neurology, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Noebels
authors.affiliation: Center for Motor Neuron Biology and Disease, Columbia University Medical Center, New York, New York 10032, USA.|Colleen Giblin Laboratory, Columbia University Medical Center, New York, New York 10032, USA.|Department of Neurology, Columbia University Medical Center, New York, New York 10032, USA.
authors.forename: Darryl C
authors.initials: DC
authors.lastname: De Vivo
authors.affiliation: Department of Pathology &Cell Biology, Columbia University Medical Center, New York, New York 10032, USA.|Center for Motor Neuron Biology and Disease, Columbia University Medical Center, New York, New York 10032, USA.|Department of Neurology, Columbia University Medical Center, New York, New York 10032, USA.
authors.forename: Umrao R
authors.initials: UR
authors.lastname: Monani
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000254:growth & development / Q000378:metabolism; D001921:Brain / Q000098:blood supply* / Q000378:metabolism / Q000503:physiopathology; D002239:Carbohydrate Metabolism, Inborn Errors / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D005260:Female; D005947:Glucose / Q000378:metabolism; D051272:Glucose Transporter Type 1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D055806:Microvessels / Q000002:abnormalities / Q000254:growth & development / Q000378:metabolism*; D009004:Monosaccharide Transport Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D018919:Neovascularization, Physiologic
chemical_list: D051272:Glucose Transporter Type 1; D009004:Monosaccharide Transport Proteins; D005947:Glucose