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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.

SUBMITTER: Tang M

PROVIDER: S-EPMC5263887 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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

Tang Maoxue M Gao Guangping G Rueda Carlos B CB Yu Hang H Thibodeaux David N DN Awano Tomoyuki T Engelstad Kristin M KM Sanchez-Quintero Maria-Jose MJ Yang Hong H Li Fanghua F Li Huapeng H Su Qin Q Shetler Kara E KE Jones Lynne L Seo Ryan R McConathy Jonathan J Hillman Elizabeth M EM Noebels Jeffrey L JL De Vivo Darryl C DC Monani Umrao R UR

Nature communications 20170120

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 co ...[more]

PMID: 28106060

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Project description:RationaleEndothelial cells (ECs) are highly glycolytic and generate the majority of their energy via the breakdown of glucose to lactate. At the same time, a main role of ECs is to allow the transport of glucose to the surrounding tissues. GLUT1 (glucose transporter isoform 1/Slc2a1) is highly expressed in ECs of the central nervous system (CNS) and is often implicated in blood-brain barrier (BBB) dysfunction, but whether and how GLUT1 controls EC metabolism and function is poorly understood.ObjectiveWe evaluated the role of GLUT1 in endothelial metabolism and function during postnatal CNS development as well as at the adult BBB.Methods and resultsInhibition of GLUT1 decreases EC glucose uptake and glycolysis, leading to energy depletion and the activation of the cellular energy sensor AMPK (AMP-activated protein kinase), and decreases EC proliferation without affecting migration. Deletion of GLUT1 from the developing postnatal retinal endothelium reduces retinal EC proliferation and lowers vascular outgrowth, without affecting the number of tip cells. In contrast, in the brain, we observed a lower number of tip cells in addition to reduced brain EC proliferation, indicating that within the CNS, organotypic differences in EC metabolism exist. Interestingly, when ECs become quiescent, endothelial glycolysis is repressed, and GLUT1 expression increases in a Notch-dependent fashion. GLUT1 deletion from quiescent adult ECs leads to severe seizures, accompanied by neuronal loss and CNS inflammation. Strikingly, this does not coincide with BBB leakiness, altered expression of genes crucial for BBB barrier functioning nor reduced vascular function. Instead, we found a selective activation of inflammatory and extracellular matrix related gene sets.ConclusionsGLUT1 is the main glucose transporter in ECs and becomes uncoupled from glycolysis during quiescence in a Notch-dependent manner. It is crucial for developmental CNS angiogenesis and adult CNS homeostasis but does not affect BBB barrier function.

Project description:BackgroundGlucose transporter 1 deficiency syndrome (Glut1DS) was initially reported by De Vivo and colleagues in 1991. This disease arises from mutations in the SLC2A1 and presents with a broad clinical spectrum. It is a treatable neuro-metabolic condition, where prompt diagnosis and initiation of ketogenic dietary therapy can markedly enhance the prognosis. However, due to its rarity, Glut1DS is susceptible to misdiagnosis or missed diagnosis, which can lead to delayed treatment and irreversible dysfunction of the central nervous system. To promote diagnostic awareness and effective treatments, the recommendations for diagnosis and treatment have been developed.MethodsThe panel on Glut1DS included 28 participants from the members of the Ketogenic Diet Professional Committee of the Chinese Epilepsy Association and Chinese experts with extensive experience in managing Glut1DS. All authors extensively reviewed the literature, and the survey results were discussed in detail over several online meetings. Following multiple deliberative sessions, all participants approved the final manuscript for submission.ResultsEarly diagnosis and timely treatment of Glut1DS are crucial for improving prognosis. Physicians should be alert to suspiction of this disease if the following clinical manifestations appear: seizures, episodic or persistent movement disorders (often triggered by fasting, fatigue, or exercise), delayed motor and cognitive development. Characteristic clinical presentations may include seizures combined with movement disorders, episodic eye-head movements, and paroxysmal exercise-induced dyskinesia (PED). In these cases, genetic testing should be promptly completed, and a lumbar puncture should be performed if necessary. The ketogenic diet is internationally recognized as the first-line treatment; the earlier it is started, the better the prognosis. It can effectively control seizures and improve motor disorders. Antiepileptic drug treatment is generally ineffective or provides limited symptom improvement before starting the ketogenic diet.ConclusionThe recommendations provide clinicians with a relatively systematic guide for the rapid identification, diagnosis, and timely treatment of Glut1DS.

Dataset Information

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

Publications

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

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