Phosphorylation of mutant huntingtin at S421 restores anterograde and retrograde transport in neurons.
Huntingtin (htt), 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 htt at serine 421 (S421) restores its function in axonal transport. Using a strategy involving RNA (ribonucleic acid) interference and re-expression of various constructs, we show that polyQ (polyglutamine)-htt is unable to promote transport of brain-derived neurotrophic factor (BDNF)-containing vesicles, but polyQ-htt constitutively phosphorylated at S421 is as effective as the wild-type (wt) as concerns transport of these vesicles. The S421 phosphorylated polyQ-htt displays the wt function of inducing BDNF release. Phosphorylation restores the interaction between htt and the p150(Glued) subunit of dynactin and their association with microtubules in vitro and in cells. We also show that the IGF-1 (insulin growth factor type I)/Akt pathway by promoting htt phosphorylation compensates for the transport defect. This is the first description of a mechanism that restores the htt function altered in disease.
Zala
Diana
D
Institut Curie, Unité Mixte de Recherche 146,F-91405 Orsay, France.
Colin
Emilie
E
Rangone
Hélène
H
Liot
Géraldine
G
Humbert
Sandrine
S
Saudou
Frédéric
F
D000818:Animals; D001370:Axonal Transport / Q000235:genetics*; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics; D002460:Cell Line; D002478:Cells, Cultured; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000503:physiopathology; D051379:Mice; D016297:Mutagenesis, Site-Directed; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism* / Q000502:physiology; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism; D010766:Phosphorylation; D021381:Protein Transport / Q000235:genetics; D051381:Rats; D012694:Serine / Q000378:metabolism*
D019208:Brain-Derived Neurotrophic Factor; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; C097188:polyglutamine; D012694:Serine