title: Glucose transporter 3 is a rab11-dependent trafficking cargo and its transport to the cell surface is reduced in neurons of CAG140 Huntington's disease mice.
abstract: Huntington's disease (HD) disturbs glucose metabolism in the brain by poorly understood mechanisms. HD neurons have defective glucose uptake, which is attenuated upon enhancing rab11 activity. Rab11 regulates numerous receptors and transporters trafficking onto cell surfaces; its diminished activity in HD cells affects the recycling of transferrin receptor and neuronal glutamate/cysteine transporter EAAC1. Glucose transporter 3 (Glut3) handles most glucose uptake in neurons. Here we investigated rab11 involvement in Glut3 trafficking. Glut3 was localized to rab11 positive puncta in primary neurons and immortalized striatal cells by immunofluorescence labeling and detected in rab11-enriched endosomes immuno-isolated from mouse brain by Western blot. Expression of dominant active and negative rab11 mutants in clonal striatal cells altered the levels of cell surface Glut3 suggesting a regulation by rab11. About 4% of total Glut3 occurred at the cell surface of primary WT neurons. HD(140Q/140Q) neurons had significantly less cell surface Glut3 than did WT neurons. Western blot analysis revealed comparable levels of Glut3 in the striatum and cortex of WT and HD(140Q/140Q) mice. However, brain slices immunolabeled with an antibody recognizing an extracellular epitope to Glut3 showed reduced surface expression of Glut3 in the striatum and cortex of HD(140Q/140Q) mice compared to that of WT mice. Surface labeling of GABAα1 receptor, which is not dependent on rab11, was not different between WT and HD(140Q/140Q) mouse brain slices. These data define Glut3 to be a rab11-dependent trafficking cargo and suggest that impaired Glut3 trafficking arising from rab11 dysfunction underlies the glucose hypometabolism observed in HD.
authors.affiliation: Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, 02129, USA. hmcclory@gmail.com.
authors.forename: Hollis
authors.initials: H
authors.lastname: McClory
authors.affiliation: Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, 02129, USA. dana.williams001@yahoo.com.
authors.forename: Dana
authors.initials: D
authors.lastname: Williams
authors.affiliation: Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, 02129, USA. esapp@mgh.harvard.edu.
authors.forename: Ellen
authors.initials: E
authors.lastname: Sapp
authors.affiliation: Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, 02129, USA. lgatune@mgh.harvard.edu.
authors.forename: Leah W
authors.initials: LW
authors.lastname: Gatune
authors.affiliation: Department of Neurology, The Second Hospital of Shandong University, Jinan, Shandong, 250033, China. pwang9@partners.org.
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
authors.affiliation: Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, 02129, USA. difiglia@helix.mgh.harvard.edu.
authors.forename: Marian
authors.initials: M
authors.lastname: DiFiglia
authors.affiliation: Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, 02129, USA. Xueyi.Li@mgh.harvard.edu.
authors.forename: Xueyi
authors.initials: X
authors.lastname: Li
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000378:metabolism*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism; D004195:Disease Models, Animal; D011992:Endosomes / Q000378:metabolism; D055879:Gene Knock-In Techniques; D051274:Glucose Transporter Type 3 / Q000378:metabolism*; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000378:metabolism*; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D021381:Protein Transport / Q000502:physiology*; D011963:Receptors, GABA-A / Q000378:metabolism; D020691:rab GTP-Binding Proteins / Q000378:metabolism*; D000099193:rab11 GTP-Binding Proteins
chemical_list: D051274:Glucose Transporter Type 3; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D011963:Receptors, GABA-A; D020691:rab GTP-Binding Proteins; D000099193:rab11 GTP-Binding Proteins; C546241:Gabra1 protein, mouse; C086055:HTT protein, human; C495689:Slc2a3 protein, mouse