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[Huntington's disease: intracellular signaling pathways and neuronal death]

Sandrine Humbert1, Frédéric Saudou

  • 1Institut Curie, CNRS UMR 146, 91405 Orsay, France. sandrine.humbert@curie.u-psud.fr

Journal De La Societe De Biologie
|February 14, 2006
PubMed

Insights

Huntington's disease (HD) involves mutant huntingtin protein impairing brain-derived neurotrophic factor (BDNF) transport, leading to neuronal death. Restoring huntingtin function may offer a therapeutic strategy for this neurodegenerative disorder.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Genetics

Background:

  • Huntington's disease (HD) is a fatal neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin gene.
  • Mutant huntingtin protein leads to neuronal dysfunction and death, but its precise mechanisms and the normal function of huntingtin are not fully understood.
  • Phosphorylation and signaling pathways like IGF-1/Akt/SGK are implicated in HD pathogenesis, influencing polyglutamine-induced toxicity.

Purpose of the Study:

  • To elucidate the function of the huntingtin protein in neuronal health.
  • To investigate the role of huntingtin in intracellular transport, specifically of brain-derived neurotrophic factor (BDNF).
  • To understand how mutant huntingtin disrupts these transport mechanisms and contributes to neurodegeneration in HD.

Main Methods:

  • Investigated the role of huntingtin in vesicular transport along microtubules.
  • Utilized biochemical assays to examine the interaction between huntingtin, Huntingtin-Associated Protein-1 (HAP1), and the p150(Glued) dynactin subunit.
  • Assessed the impact of wild-type and mutant huntingtin on BDNF transport and neuronal survival.

Main Results:

  • Huntingtin enhances the vesicular transport of BDNF along microtubules, a process involving HAP1 and p150(Glued).
  • BDNF transport is significantly reduced in HD models and when wild-type huntingtin levels are decreased.
  • The huntingtin/HAP1/p150(Glued) complex disruption in HD correlates with motor protein detachment from microtubules, leading to impaired neurotrophic support and neuronal toxicity.

Conclusions:

  • Huntingtin is crucial for the efficient transport of BDNF, essential for neuronal survival.
  • Defective BDNF transport due to mutant huntingtin contributes significantly to the neurodegenerative process in Huntington's disease.
  • Targeting the huntingtin-mediated transport pathway may offer a novel therapeutic approach for HD.

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