期刊
NEUROBIOLOGY OF DISEASE
卷 36, 期 2, 页码 374-383出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.nbd.2009.08.003
关键词
Huntingtin; Knock-in mouse; Rab11
资金
- Hereditary Disease Foundation
- High Q/CHDI Foundation
- NIH [NS35711, NS38194]
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 Rab11 GTP 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. (C) 2009 Elsevier Inc. All rights reserved.
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