Disruption of Rab protein vesicle transport by loss of huntingtin in vivo. Shermali D. Gunawardena, Derek Power, Shruthi Srinivasan. Biological Sciences, SUNY at Buffalo, Buffalo, NY.

   Previous work put forth a tantalizing proposal that disruption of axonal transport within long, narrow-caliber axons caused accumulations that could elicit cell death, ultimately resulting in neuronal dysfunction observed in Huntingtons Disease. Although a role for the Huntingtons disease protein huntingtin (HTT) has been reported in axonal transport, it is unclear if HTT affects the transport of all vesicles or if HTT affects a specific class of vesicles. In this context, here we tested the hypothesis that disruption of Rab protein vesicle transport within axons mediated by HTT can contribute to early neuropathology observed in HD. Using in vivo motility analysis we found that HTT influences Rab11, Rab32 and Rab4X vesicles, but not Rab5 vesicles. While reduction of HTT perturbed the transport of Rab 11 and Rab32 vesicles, reduction of HTT rescued RabX4-mediated transport defects. Although Rab11, Rab32 and RabX4 are all thought to be on recycling endosomes, while Rab 5 is on early endosomes, all these Rab proteins show bi-directional movement. Reductions in kinesin and dynein motors also perturbed Rab11 vesicle transport indicating that these motors are required for bi-directional transport of Rab11. These results suggest that HTT plays a key role in the movement of Rab11, Rab32 and Rab4 vesicles within axons. Thus disruption of Rab vesicle transport mediated by mutant HTT could contribute to early neuropathology observed in Huntington's diseases.