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

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

来源：Neurobiology of Disease, 2009, 36(2): 374-383.

DOI：10.1016/j.nbd.2009.08.003

• Huntingtin
• Knock-in mouse
• Rab11

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 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.

• 出版日期2009-11