title: In-vivo evidence for the disruption of Rab11 vesicle transport by loss of huntingtin.
abstract: The neuropathology of Huntington's disease includes nuclear and cytoplasmic inclusions, striatal neuronal loss, and gliosis. Previous work put forward 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. Although a role for the Huntington's disease protein huntingtin (HTT) has been reported in axonal transport, it is unclear whether HTT affects the transport of all vesicles or influences only a specific class of vesicles. As an interaction between HTT and Rab5 was previously shown to mediate transport on actin filaments, here we tested the hypothesis that a HTT-Rab5 complex also exists for transport on microtubules during axonal transport. Surprisingly, we found that HTT influences Rab11 vesicles, not Rab5 vesicles. Reduction of HTT perturbed the transport of Rab11 vesicles. Reductions in kinesin and dynein motors also perturbed Rab11 vesicle transport indicating that these motors are required for bidirectional transport of Rab11. These results suggest that HTT plays a key role in the movement of Rab11 vesicles within axons. Thus, disruption of transport mediated by mutant HTT could contribute to early neuropathology observed in Huntington's diseases.
authors.affiliation: Department of Biological Sciences, The State University of New York at Buffalo, Buffalo, New York 14260, USA.
authors.forename: Derek
authors.initials: D
authors.lastname: Power
authors.forename: Shruthi
authors.initials: S
authors.lastname: Srinivasan
authors.forename: Shermali
authors.initials: S
authors.lastname: Gunawardena
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001370:Axonal Transport / Q000235:genetics*; D022162:Cytoplasmic Vesicles / Q000235:genetics* / Q000378:metabolism; D029721:Drosophila Proteins / Q000172:deficiency* / Q000235:genetics*; D004331:Drosophila melanogaster; D005260:Female; D055785:Gene Knockdown Techniques / Q000379:methods; D000071058:Huntingtin Protein; D008297:Male; D008869:Microtubule-Associated Proteins / Q000172:deficiency* / Q000235:genetics*; D020691:rab GTP-Binding Proteins / Q000172:deficiency* / Q000235:genetics*; D000099193:rab11 GTP-Binding Proteins
chemical_list: D029721:Drosophila Proteins; D000071058:Huntingtin Protein; D008869:Microtubule-Associated Proteins; D020691:rab GTP-Binding Proteins; C542005:Htt protein, Drosophila; C559123:Rab11 protein, Drosophila; D000099193:rab11 GTP-Binding Proteins