Huntingtin Controls Neurotrophic Support and Survival of Neurons by Enhancing BDNF Vesicular Transport Along Microtubules

Cell. 2004 Jul 9;118(1):127-38. doi: 10.1016/j.cell.2004.06.018.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 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
  • Huntingtin Protein
  • Mice
  • Microtubule-Associated Proteins / metabolism
  • Microtubules / metabolism*
  • Models, Biological
  • Nerve Tissue Proteins / metabolism*
  • Neurons / metabolism*
  • Neurons / pathology
  • Nuclear Proteins / metabolism*

Substances

  • Brain-Derived Neurotrophic Factor
  • DNA-Binding Proteins
  • Dctn1 protein, mouse
  • Dynactin Complex
  • Hip1 protein, mouse
  • Htt protein, mouse
  • Huntingtin Protein
  • Microtubule-Associated Proteins
  • Nerve Tissue Proteins
  • Nuclear Proteins