Huntingtin differentially regulates the axonal transport of a sub-set of Rab-containing vesiclesin vivo

Abstract

Loss of huntingtin (HTT), the Huntington's disease (HD) protein, was previously shown to cause axonal transport defects. Within axons, HTT can associate with kinesin-1 and dynein motors either directly or via accessory proteins for bi-directional movement. However, the composition of the vesicle-motor complex that contains HTT during axonal transport is unknown. Here we analyze the in vivo movement of 16 Rab GTPases within Drosophila larval axons and show that HTT differentially influences the movement of a particular sub-set of these Rab-containing vesicles. While reduction of HTT perturbed the bi-directional motility of Rab3 and Rab19-containing vesicles, only the retrograde motility of Rab7-containing vesicles was disrupted with reduction of HTT. Interestingly, reduction of HTT stimulated the anterograde motility of Rab2-containing vesicles. Simultaneous dual-view imaging revealed that HTT and Rab2, 7 or 19 move together during axonal transport. Collectively, our findings indicate that HTT likely influences the motility of different Rab-containing vesicles and Rab-mediated functions. These findings have important implications for our understanding of the complex role HTT plays within neurons normally, which when disrupted may lead to neuronal death and disease.

The many disguises of the signalling endosome

“…In agreement with this model, expression of polyQ‐Htt reduces the retrograde transport of TrkB‐BDNF complexes in dendrites of striatal neurons . In addition, reduction of wild‐type Htt expression inhibits the retrograde transport of Rab7‐positive vesicles in Drosophila larval axons .…”

Golgi trafficking defects in postnatal microcephaly: The evidence for “Golgipathies”

“…If you believe that this document breaches copyright please contact librarypure@kcl.ac.uk providing details, and we will remove access to the work immediately and investigate your claim. Regulation of GA morphology, Axonal transport (Aizawa and Fukuda, 2015;White et al, 2015)…”

Emerging nexus between RAB GTPases, autophagy and neurodegeneration

“…For example, wild-type HTT is required for movement of RAB7A-positive vesicles through neurons of a Drosophila model of Huntington disease. 19 Any perturbation of HTT activity might thus impact RAB7A-mediated autophagy, and could be a cause of buildup of uncleared autophagosomes in Huntington disease. Another instance where a disease-associated protein regulates autophagy through RAB activity is that of LRRK1 (leucine-rich repeat kinase 1) involved in Parkinson disease (PD).…”