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Mutant Huntingtin Impairs Vesicle Formation from Recycling Endosomes by Interfering with Rab11 Activity

Mutant Huntingtin Impairs Vesicle Formation from Recycling Endosomes by Interfering with Rab11... Mutant Huntingtin Impairs Vesicle Formation from Recycling Endosomes by Interfering with Rab11 Activity ▿ † Xueyi Li 1 , Clive Standley 2 , Ellen Sapp 1 , Antonio Valencia 1 , Zheng-Hong Qin 1 , Kimberly B. Kegel 1 , Jennifer Yoder 1 , Laryssa A. Comer-Tierney 1 , Miguel Esteves 1 , Kathryn Chase 3 , Jonathan Alexander 1 , Nicholas Masso 1 , Lindsay Sobin 1 , Karl Bellve 2 , Richard Tuft 2 , Lawrence Lifshitz 2 , Kevin Fogarty 2 , Neil Aronin 3 , * and Marian DiFiglia 1 1 Cellular Neurobiology Laboratory and Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129 2 Biomedical Imaging Group, Department of Physiology, University of Massachusetts Medical School 3 Department of Medicine and Cell Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01655 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. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Molecular and Cellular Biology American Society For Microbiology

Mutant Huntingtin Impairs Vesicle Formation from Recycling Endosomes by Interfering with Rab11 Activity

Molecular and Cellular Biology , Volume 29 (22): 6106 – Nov 15, 2009

Abstract

Mutant Huntingtin Impairs Vesicle Formation from Recycling Endosomes by Interfering with Rab11 Activity ▿ † Xueyi Li 1 , Clive Standley 2 , Ellen Sapp 1 , Antonio Valencia 1 , Zheng-Hong Qin 1 , Kimberly B. Kegel 1 , Jennifer Yoder 1 , Laryssa A. Comer-Tierney 1 , Miguel Esteves 1 , Kathryn Chase 3 , Jonathan Alexander 1 , Nicholas Masso 1 , Lindsay Sobin 1 , Karl Bellve 2 , Richard Tuft 2 , Lawrence Lifshitz 2 , Kevin Fogarty 2 , Neil Aronin 3 , * and Marian DiFiglia 1 1 Cellular Neurobiology Laboratory and Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129 2 Biomedical Imaging Group, Department of Physiology, University of Massachusetts Medical School 3 Department of Medicine and Cell Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01655 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.

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References (57)

Publisher
American Society For Microbiology
Copyright
Copyright © 2009 by the American society for Microbiology.
ISSN
0270-7306
eISSN
1098-5549
DOI
10.1128/MCB.00420-09
pmid
19752198
Publisher site
See Article on Publisher Site

Abstract

Mutant Huntingtin Impairs Vesicle Formation from Recycling Endosomes by Interfering with Rab11 Activity ▿ † Xueyi Li 1 , Clive Standley 2 , Ellen Sapp 1 , Antonio Valencia 1 , Zheng-Hong Qin 1 , Kimberly B. Kegel 1 , Jennifer Yoder 1 , Laryssa A. Comer-Tierney 1 , Miguel Esteves 1 , Kathryn Chase 3 , Jonathan Alexander 1 , Nicholas Masso 1 , Lindsay Sobin 1 , Karl Bellve 2 , Richard Tuft 2 , Lawrence Lifshitz 2 , Kevin Fogarty 2 , Neil Aronin 3 , * and Marian DiFiglia 1 1 Cellular Neurobiology Laboratory and Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129 2 Biomedical Imaging Group, Department of Physiology, University of Massachusetts Medical School 3 Department of Medicine and Cell Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01655 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.

Journal

Molecular and Cellular BiologyAmerican Society For Microbiology

Published: Nov 15, 2009

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