[HTML][HTML] Huntingtin controls neurotrophic support and survival of neurons by enhancing BDNF vesicular transport along microtubules

LR Gauthier, BC Charrin, M Borrell-Pagès… - Cell, 2004 - cell.com
LR Gauthier, BC Charrin, M Borrell-Pagès, JP Dompierre, H Rangone, FP Cordelières…
Cell, 2004cell.com
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 …
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 p150Glued 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/p150Glued 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.
cell.com