Article
- The EMBO Journal (2008) 27, 2124 - 2134
- doi:10.1038/emboj.2008.133
Published online: 10 July 2008
Subject Categories:
Huntingtin phosphorylation acts as a molecular switch for anterograde/retrograde transport in neurons
Emilie Colin1,2,a, Diana Zala1,2,a, Géraldine Liot1,2, Hélène Rangone1,2,b, Maria Borrell-Pagès1,2,c, Xiao-Jiang Li3, Frédéric Saudou1,2 and Sandrine Humbert1,2
- Institut Curie, Orsay, France
- CNRS UMR146, Orsay, France
- Department of Human Genetics, Emory University, Atlanta, GA, USA
Correspondence to:
Frédéric Saudou, CNRS UMR146, Institut Curie, bat.110, centre universitaire, Orsay F-91400, France. Tel.: +33 169 863 024; Fax: +33 169 863 051; E-mail: Frederic.Saudou@curie.fr
Sandrine Humbert, CNRS UMR146, Institut Curie, bat.110, centre universitaire, Orsay F-91400, France. Tel.: +33 169 863 024; Fax: +33 169 863 051; E-mail: sandrine.humbert@curie.fr
aThese authors contributed equally to this work
bPresent address: Department of Genetics, University of Cambridge, Cambridge CB23EH, UK
cPresent address: Cardiovascular Research Center, CSIC-ICCC, Hospital de la Santa Creu I Sant Pau, Barcelona, Spain
Received 21 February 2008; Accepted 17 June 2008
Abstract
The transport of vesicles in neurons is a highly regulated process, with vesicles moving either anterogradely or retrogradely depending on the nature of the molecular motors, kinesins and dynein, respectively, which propel vesicles along microtubules (MTs). However, the mechanisms that determine the directionality of transport remain unclear. Huntingtin, the protein mutated in Huntington's disease, is a positive regulatory factor for vesicular transport. Huntingtin is phosphorylated at serine 421 by the kinase Akt but the role of this modification is unknown. Here, we demonstrate that phosphorylation of wild-type huntingtin at S421 is crucial to control the direction of vesicles in neurons. When phosphorylated, huntingtin recruits kinesin-1 to the dynactin complex on vesicles and MTs. Using brain-derived neurotrophic factor as a marker of vesicular transport, we demonstrate that huntingtin phosphorylation promotes anterograde transport. Conversely, when huntingtin is not phosphorylated, kinesin-1 detaches and vesicles are more likely to undergo retrograde transport. This also applies to other vesicles suggesting an essential role for huntingtin in the control of vesicular directionality in neurons.
Keywords:
- APP,
- BDNF,
- dynactin,
- dynein,
- kinesin-1
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