Huntingtin controls neurotrophic support and survival of neurons by enhancing BDNF vesicular transport along microtubules.
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.
Gauthier
Laurent R
LR
Unité Mixte de Recherche 146, Centre National de la Recherche Scientifique, Institut Curie, Building 110, Centre Universitaire, 91405 Orsay Cedex, France.
Charrin
Bénédicte C
BC
Borrell-Pagès
Maria
M
Dompierre
Jim P
JP
Rangone
Hélène
H
Cordelières
Fabrice P
FP
De Mey
Jan
J
MacDonald
Marcy E
ME
Lessmann
Volkmar
V
Humbert
Sandrine
S
Saudou
Frédéric
F
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*
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