Disruption of Rab11 activity in a knock-in mouse model of Huntington's disease

Xueyi Li; Ellen Sapp; Kathryn Chase; Laryssa A. Comer-Tierney; Nicholas Masso; Jonathan Alexander; Patrick Reeves; Kimberly B. Kegel; Antonio Valencia; Miguel Esteves; Neil Aronin; Marian DiFiglia

Neurobiology of Disease (Nov 2009)

Disruption of Rab11 activity in a knock-in mouse model of Huntington's disease

Xueyi Li,
Ellen Sapp,
Kathryn Chase,
Laryssa A. Comer-Tierney,
Nicholas Masso,
Jonathan Alexander,
Patrick Reeves,
Kimberly B. Kegel,
Antonio Valencia,
Miguel Esteves,
Neil Aronin,
Marian DiFiglia

Affiliations

Xueyi Li: Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA; Corresponding authors. M. DiFiglia is to be contacted at Cellular Neurobiology Laboratory and Department of Neurology, Massachusetts General Hospital Harvard Medical School, Charlestown, MA 02129, USA. Fax: +1 617 726 1264.
Ellen Sapp: Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA
Kathryn Chase: Department of Medicine and Cell Biology, University of Massachusetts Medical School, Worcester, MA 01655, USA
Laryssa A. Comer-Tierney: Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA
Nicholas Masso: Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA
Jonathan Alexander: Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA
Patrick Reeves: Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA
Kimberly B. Kegel: Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA
Antonio Valencia: Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA
Miguel Esteves: Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA
Neil Aronin: Department of Medicine and Cell Biology, University of Massachusetts Medical School, Worcester, MA 01655, USA
Marian DiFiglia: Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA; Corresponding authors. M. DiFiglia is to be contacted at Cellular Neurobiology Laboratory and Department of Neurology, Massachusetts General Hospital Harvard Medical School, Charlestown, MA 02129, USA. Fax: +1 617 726 1264.

Journal volume & issue: Vol. 36, no. 2
pp. 374 – 383

Abstract

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The Huntington's disease (HD) mutation causes polyglutamine expansion in huntingtin (Htt) and neurodegeneration. Htt interacts with a complex containing Rab11GDP and is involved in activation of Rab11, which functions in endosomal recycling and neurite growth and long-term potentiation. Like other Rab proteins, Rab11GDP undergoes nucleotide exchange to Rab11GTP for its activation. Here we show that striatal membranes of HD140Q/140Q knock-in mice are impaired in supporting conversion of Rab11GDP to Rab11GTP. Dominant negative Rab11 expressed in the striatum and cortex of normal mice caused neuropathology and motor dysfunction, suggesting that a deficiency in Rab11 activity is pathogenic in vivo. Primary cortical neurons from HD140Q/140Q mice were delayed in recycling transferrin receptors back to the plasma membrane. Partial rescue from glutamate-induced cell death occurred in HD neurons expressing dominant active Rab11. We propose a novel mechanism of HD pathogenesis arising from diminished Rab11 activity at recycling endosomes.

Published in Neurobiology of Disease

ISSN: 0969-9961 (Print); 1095-953X (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Internal medicine: Neurosciences. Biological psychiatry. Neuropsychiatry
Website: https://www.journals.elsevier.com/neurobiology-of-disease

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