[Huntington's disease: intracellular signaling pathways and neuronal death].
Huntington's disease (HD) is a mid-life onset neurodegenerative disorder characterized by unvoluntary movements (chorea), personality changes and dementia that progress to death within 10-20 years of onset. There are currently no treatment to delay or prevent appearance of the symptoms in the patients. The defective gene in HD contains a trinucleotide CAG repeat expansion within its coding region that is expressed as a polyglutamine (polyQ) repeat in the protein huntingtin. The exact molecular mechanims by which mutant huntingtin induces cell death as well as the function of huntingtin are not totally understood. Studying mechanisms by which polyQ-huntingtin induces neurodegeneration has shown that phosphorylation plays a key role in HD. The IGF-1/Akt/SGK pathway reduces polyQ-huntingtin induced toxicity. This anti-apopototic effect is mediated via the phosphorylation of serine 421 of huntingtin. Moreover, components of this pathway are altered in disease. What is the function of huntingtin? Several studies indicate that huntingtin is an anti-apoptotic protein that could regulate intracellular dynamic. We recently demonstrated, 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, polyQ-huntingtin-induced transport deficit results in the loss of neurotrophic support and neuronal toxicity.
Institut Curie, CNRS UMR 146, 91405 Orsay, France. sandrine.humbert@curie.u-psud.fr
Sandrine
S
Humbert
Frédéric
F
Saudou
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D001370:Axonal Transport / Q000502:physiology; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D000072159:Dynactin Complex; D047108:Embryonic Development / Q000502:physiology; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000473:pathology* / Q000503:physiopathology; D007334:Insulin-Like Growth Factor I / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008870:Microtubules / Q000502:physiology; D008959:Models, Neurological; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000378:metabolism / Q000502:physiology; D009474:Neurons / Q000473:pathology*; D009687:Nuclear Proteins / Q000737:chemistry / Q000502:physiology; D051058:Oncogene Protein v-akt / Q000502:physiology; D010455:Peptides / Q000235:genetics; D010766:Phosphorylation; D010768:Phosphoserine / Q000737:chemistry; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D015398:Signal Transduction; D018911:Trinucleotide Repeats
D051017:Apoptosis Regulatory Proteins; D019208:Brain-Derived Neurotrophic Factor; C000606360:DCTN1 protein, human; C000606364:Dctn1 protein, mouse; D000072159:Dynactin Complex; C096896:HAP1 protein, human; C086055:HTT protein, human; D000071058:Huntingtin Protein; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; D010768:Phosphoserine; C097188:polyglutamine; D007334:Insulin-Like Growth Factor I; D051058:Oncogene Protein v-akt