title: Huntingtin controls neurotrophic support and survival of neurons by enhancing BDNF vesicular transport along microtubules.
abstract: Polyglutamine expansion (polyQ) in the protein huntingtin is pathogenic and responsible for the neuronal toxicity associated with Huntington's disease (HD). Although wild-type huntingtin possesses antiapoptotic properties, the relationship between the neuroprotective functions of huntingtin and pathogenesis of HD remains unclear. Here, we show that huntingtin specifically enhances vesicular transport of brain-derived neurotrophic factor (BDNF) along microtubules. Huntingtin-mediated transport involves huntingtin-associated protein-1 (HAP1) and the p150(Glued) subunit of dynactin, an essential component of molecular motors. BDNF transport is attenuated both in the disease context and by reducing the levels of wild-type huntingtin. The alteration of the huntingtin/HAP1/p150(Glued) complex correlates with reduced association of motor proteins with microtubules. Finally, we find that the polyQ-huntingtin-induced transport deficit results in the loss of neurotrophic support and neuronal toxicity. Our findings indicate that a key role of huntingtin is to promote BDNF transport and suggest that loss of this function might contribute to pathogenesis.
authors.affiliation: Unité Mixte de Recherche 146, Centre National de la Recherche Scientifique, Institut Curie, Building 110, Centre Universitaire, 91405 Orsay Cedex, France.
authors.forename: Laurent R
authors.initials: LR
authors.lastname: Gauthier
authors.forename: Bénédicte C
authors.initials: BC
authors.lastname: Charrin
authors.forename: Maria
authors.initials: M
authors.lastname: Borrell-Pagès
authors.forename: Jim P
authors.initials: JP
authors.lastname: Dompierre
authors.forename: Hélène
authors.initials: H
authors.lastname: Rangone
authors.forename: Fabrice P
authors.initials: FP
authors.lastname: Cordelières
authors.forename: Jan
authors.initials: J
authors.lastname: De Mey
authors.forename: Marcy E
authors.initials: ME
authors.lastname: MacDonald
authors.forename: Volkmar
authors.initials: V
authors.lastname: Lessmann
authors.forename: Sandrine
authors.initials: S
authors.lastname: Humbert
authors.forename: Frédéric
authors.initials: F
authors.lastname: Saudou
mesh_terms: D000818:Animals; D001692:Biological Transport; D001921:Brain / Q000473:pathology; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D002470:Cell Survival; D002478:Cells, Cultured; D022162:Cytoplasmic Vesicles / Q000737:chemistry / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D000072159:Dynactin Complex; D000071058:Huntingtin Protein; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008870:Microtubules / Q000378:metabolism*; D008954:Models, Biological; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D009687:Nuclear Proteins / Q000378:metabolism*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D004268:DNA-Binding Proteins; C000606364:Dctn1 protein, mouse; D000072159:Dynactin Complex; C489536:Hip1 protein, mouse; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins