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...

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Bibliographic Details
Published in:Cell 2004-07, Vol.118 (1), p.127-138
Main Authors: Gauthier, Laurent R, Charrin, Bénédicte C, Borrell-Pagès, Maria, Dompierre, Jim P, Rangone, Hélène, Cordelières, Fabrice P, De Mey, Jan, MacDonald, Marcy E, Leßmann, Volkmar, Humbert, Sandrine, Saudou, Frédéric
Format: Article
Language:English
Subjects:
Animals
Biological Transport
Brain - pathology
Brain-Derived Neurotrophic Factor - metabolism
Cell Survival
Cells, Cultured
Cytoplasmic Vesicles - chemistry
Cytoplasmic Vesicles - metabolism
DNA-Binding Proteins - metabolism
Dynactin Complex
Mice
Microtubule-Associated Proteins - metabolism
Microtubules - metabolism
Models, Biological
Nerve Tissue Proteins - metabolism
Neurons - metabolism
Neurons - pathology
Nuclear Proteins - metabolism
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Summary: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.
ISSN:0092-8674
1097-4172
DOI:10.1016/j.cell.2004.06.018