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Grenoble Institut des Neurosciences Grenoble Institut des Neurosciences

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Huntington’s disease and the role of huntingtin phosphorylation in the control of axonal transport

Objectifs

The objectives of the project are to understand the role of the huntingtin protein in the regulation of intracellular dynamics in neurons in response to trophic factors.

Résumé

Huntington’s disease (HD) is caused by the abnormal polyglutamine expansion in the N-ter part of huntingtin (HTT), a large protein of 350kDa. Over the past years, we proposed that HTT acts a scaffold for the molecular motors and through this function, regulates the efficiency of vesicular transport along microtubules in neurons. We also showed that HTT phosphorylation acts as a molecular switch to control transport directionality in axons. Here we propose to study the signaling cascade resulting in the specific retrograde routing of signaling endosomes within axons through HTT phosphorylation. This mechanism being key to control neuronal survival, we will also study alterations of this pathway in HD.

Méthodes

Techniques used will include molecular biology, biochemistry, primary cultures, state of the art live-imaging microscopy and the development and use of new microfluidic devices to study intracellular dynamics in connected neuronal networks.

Références

  • Hinckelmann MV, et al., (2016) Self-propelling vesicles define glycolysis as the minimal energy machinery for neuronal transport Nature Communications, 7:13233. doi: 10.1038/ncomms13233.
  • El-Daher MT et al. (2015) Huntingtin proteolysis releases non-polyQ fragments that cause toxicity through dynamin 1 dysregulation. EMBO J. 34(17):2255-71. doi: 10.15252/embj.201490808.
  • Zala D, et al. (2013) Vesicular glycolysis provides on-board energy for axonal transport. Cell. 152, 479-91. doi: 10.1016/j.cell.2012.12.029.

Contacts

Frédéric Saudou, PU-PH1 UGA & Chiara Scaramuzzino, Chercheur Inserm
Email : Frederic.Saudou@univ-grenoble-alpes.fr
Mise à jour le 23 mai 2017

Contacts

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