title: Disruption of Rab11 activity in a knock-in mouse model of Huntington's disease.
abstract: 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 HD(140Q/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 HD(140Q/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.
authors.affiliation: Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA. xli12@partners.org
authors.forename: Xueyi
authors.initials: X
authors.lastname: Li
authors.forename: Ellen
authors.initials: E
authors.lastname: Sapp
authors.forename: Kathryn
authors.initials: K
authors.lastname: Chase
authors.forename: Laryssa A
authors.initials: LA
authors.lastname: Comer-Tierney
authors.forename: Nicholas
authors.initials: N
authors.lastname: Masso
authors.forename: Jonathan
authors.initials: J
authors.lastname: Alexander
authors.forename: Patrick
authors.initials: P
authors.lastname: Reeves
authors.forename: Kimberly B
authors.initials: KB
authors.lastname: Kegel
authors.forename: Antonio
authors.initials: A
authors.lastname: Valencia
authors.forename: Miguel
authors.initials: M
authors.lastname: Esteves
authors.forename: Neil
authors.initials: N
authors.lastname: Aronin
authors.forename: Marian
authors.initials: M
authors.lastname: Difiglia
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000235:genetics; D002460:Cell Line; D002478:Cells, Cultured; D004195:Disease Models, Animal; D011992:Endosomes / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D055879:Gene Knock-In Techniques; D006816:Huntington Disease / Q000209:etiology / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008818:Mice, Neurologic Mutants; D020691:rab GTP-Binding Proteins / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D000099193:rab11 GTP-Binding Proteins
chemical_list: D020691:rab GTP-Binding Proteins; D000099193:rab11 GTP-Binding Proteins
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