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Neurobiol Dis. 2009 Nov;36(2):374-83. doi: 10.1016/j.nbd.2009.08.003. Epub 2009 Aug 20.

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

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  • 1Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA. xli12@partners.org

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.

PMID:
19699304
PMCID:
PMC2798579
DOI:
10.1016/j.nbd.2009.08.003
[PubMed - indexed for MEDLINE]
Free PMC Article
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