Disruption of Rab11 activity in a knock-in mouse model of Huntington's disease.
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.
Li
Xueyi
X
Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA. xli12@partners.org
Sapp
Ellen
E
Chase
Kathryn
K
Comer-Tierney
Laryssa A
LA
Masso
Nicholas
N
Alexander
Jonathan
J
Reeves
Patrick
P
Kegel
Kimberly B
KB
Valencia
Antonio
A
Esteves
Miguel
M
Aronin
Neil
N
Difiglia
Marian
M
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
D020691:rab GTP-Binding Proteins; D000099193:rab11 GTP-Binding Proteins
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