title: Mutant huntingtin impairs vesicle formation from recycling endosomes by interfering with Rab11 activity.
abstract: Huntingtin (Htt) localizes to endosomes, but its role in the endocytic pathway is not established. Recently, we found that Htt is important for the activation of Rab11, a GTPase involved in endosomal recycling. Here we studied fibroblasts of healthy individuals and patients with Huntington's disease (HD), which is a movement disorder caused by polyglutamine expansion in Htt. The formation of endocytic vesicles containing transferrin at plasma membranes was the same in control and HD patient fibroblasts. However, HD fibroblasts were delayed in recycling biotin-transferrin back to the plasma membrane. Membranes of HD fibroblasts supported less nucleotide exchange on Rab11 than did control membranes. Rab11-positive vesicular and tubular structures in HD fibroblasts were abnormally large, suggesting that they were impaired in forming vesicles. We used total internal reflection fluorescence imaging of living fibroblasts to monitor fluorescence-labeled transferrin-carrying transport intermediates that emerged from recycling endosomes. HD fibroblasts had fewer small vesicles and more large vesicles and long tubules than did control fibroblasts. Dominant active Rab11 expressed in HD fibroblasts normalized the recycling of biotin-transferrin. We propose a novel mechanism for cellular dysfunction by the HD mutation arising from the inhibition of Rab11 activity and a deficit in vesicle formation at recycling endosomes.
authors.affiliation: Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, USA.
authors.forename: Xueyi
authors.initials: X
authors.lastname: Li
authors.forename: Clive
authors.initials: C
authors.lastname: Standley
authors.forename: Ellen
authors.initials: E
authors.lastname: Sapp
authors.forename: Antonio
authors.initials: A
authors.lastname: Valencia
authors.forename: Zheng-Hong
authors.initials: ZH
authors.lastname: Qin
authors.forename: Kimberly B
authors.initials: KB
authors.lastname: Kegel
authors.forename: Jennifer
authors.initials: J
authors.lastname: Yoder
authors.forename: Laryssa A
authors.initials: LA
authors.lastname: Comer-Tierney
authors.forename: Miguel
authors.initials: M
authors.lastname: Esteves
authors.forename: Kathryn
authors.initials: K
authors.lastname: Chase
authors.forename: Jonathan
authors.initials: J
authors.lastname: Alexander
authors.forename: Nicholas
authors.initials: N
authors.lastname: Masso
authors.forename: Lindsay
authors.initials: L
authors.lastname: Sobin
authors.forename: Karl
authors.initials: K
authors.lastname: Bellve
authors.forename: Richard
authors.initials: R
authors.lastname: Tuft
authors.forename: Lawrence
authors.initials: L
authors.lastname: Lifshitz
authors.forename: Kevin
authors.initials: K
authors.lastname: Fogarty
authors.forename: Neil
authors.initials: N
authors.lastname: Aronin
authors.forename: Marian
authors.initials: M
authors.lastname: DiFiglia
mesh_terms: D000293:Adolescent; D000328:Adult; D001710:Biotin / Q000378:metabolism; D002478:Cells, Cultured; D002648:Child; D022163:Clathrin-Coated Vesicles / Q000378:metabolism; D004705:Endocytosis; D011992:Endosomes / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D004789:Enzyme Activation; D005347:Fibroblasts / Q000201:enzymology / Q000473:pathology; D005799:Genes, Dominant; D006801:Humans; D000071058:Huntingtin Protein; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D050505:Mutant Proteins / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D021381:Protein Transport; D011990:Receptors, Transferrin / Q000378:metabolism; D013194:Staining and Labeling; D014168:Transferrin / Q000378:metabolism; D020691:rab GTP-Binding Proteins / Q000378:metabolism*; D000099193:rab11 GTP-Binding Proteins
chemical_list: D001710:Biotin; D000071058:Huntingtin Protein; D050505:Mutant Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D011990:Receptors, Transferrin; D014168:Transferrin; D020691:rab GTP-Binding Proteins; D000099193:rab11 GTP-Binding Proteins; C086055:HTT protein, human