Human Molecular Genetics Advance Access published online on September 4, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn281
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Phosphorylation of mutant huntingtin at S421 restores anterograde and retrograde transport in neurons
1 Institut Curie and Unité Mixte de Recherche 146, F-91405 Orsay, France 2 Centre National de la Recherche Scientifique, Unité Mixte de Recherche 146, F-91405 Orsay, France
* To whom correspondence should be addressed. E-mail: Sandrine.Humbert{at}curie.fr
Received July 25, 2008; Revised September 2, 2008; Accepted September 2, 2008
Huntingtin, the protein mutated in Huntington's disease, is a positive regulatory factor for vesicular transport whose function is lost in disease. Here, we demonstrate that phosphorylation of huntingtin at serine 421 (S421) restores its function in axonal transport. Using a strategy involving RNA interference and re-expression of various constructs, we show that polyQ-huntingtin is unable to promote transport of brain-derived neurotrophic factor (BDNF)-containing vesicles, but polyQ-huntingtin constitutively phosphorylated at S421 is as effective as the wild-type as concerns transport of these vesicles. The S421 phosphorylated polyQ-htt displays the wild-type function of inducing BDNF release. Phosphorylation restores the interaction between huntingtin and the p150Glued subunit of dynactin and their association to microtubules in vitro and in cells. We also show that the IGF-1/Akt pathway by promoting huntingtin phosphorylation compensates for the transport defect. This is the first description of a mechanism that restores the huntingtin function altered in disease.
3 These authors contributed equally to this work
4 Present address: Department of ophthalmology, Jules Stein Eye Institute, UCLA, Los Angeles, California
5 Present address: Department of Genetics, University of Cambridge, Cambridge, CB23EH UK.
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