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Grenoble Institut des Neurosciences Grenoble Institut des Neurosciences

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Team "Intracellular Dynamics and Neurodegeneration"

Director: Frédéric SAUDOU

Our goal is to elucidate the molecular mechanisms by which mutant HTT induces neurodegeneration. In particular, our team focuses on the understanding of HTT function/dysfunction in the control of intracellular dynamics related to cell homeostasis and neurotrophin signaling.

The Team "Intracellular Dynamics and Neurodegeneration" has proposed a major role of HTT in the regulation of fast axonal transport (FAT) and found that HTT regulates efficacy and the directionality of FAT through phosphorylations. In addition the team has shown that these phosphorylations restore FAT in the disease situation.

Research themes

Huntingtin protein mutation consists in the addition of an abnormally high number of the amino acid Glutamine which creates a polyGlutamine repetition. This expansion is at the origing of Huntington's Disease, a rare hereditary neurodegenerative disorder rare that progressively leads to motor deficits, cognitive decline ans psychiatric troubles.

To better understand the molecular mechanisms by which the huntingtin protein regulates intracellular dynamics and neuronal functions, the team works around these two research projects :

  • Studying the normal functions of huntingtin and its role on neuronal functions : To better understand how huntingtin controls vesicular transport in axons and the consequences on physiological functions of the neuron.
  • Dysfunctional consequences of polyGlutamine expansion : To determine how abnormal repetition of Glutamines alters the normal functions of hutingtin and the consequences on intracellular dynamics.

Techniques

  • Cell and molecular biology : primary cultures of neurones, expression of recombinant proteins, protein-protein interactions, fluorescent probes and sensors

  • Microscopy : spinning-disk videomicroscopy, confocal, super-resolution, 2-photon

  • Microfluidics : neuronal networks, axonal transport, synapses, axonal growth

  • Electrophysiology : microelectrode arrays, patch clamp, optogenetics

  • Development of drosophila and transgenic mice : knock-in, mutants, Huntington models

Publications

Main publications in peer-reviewed international journals

An integrated microfluidic/microelectrode array for the study of activity-dependent intracellular dynamics in neuronal networks.Moutaux E, Charlot B, Genoux A, Saudou F, Cazorla M. Lab Chip. 2018 Nov 6;18(22):3425-3435.

Neuronal network maturation differently affects secretory vesicles and mitochondria transport in axons. Moutaux E, Christaller W, Scaramuzzino C, Genoux A, Charlot B, Cazorla M*, Saudou F*. Sci Rep. 2018 Sep 7;8(1):13429.

Region-specific and state-dependent action of striatal GABAergic interneurons. Fino E, Vandecasteele M, Perez S, Saudou F, Venance L. Nat Commun. 2018 Aug 21;9(1):3339.

Reconstituting Corticostriatal Network on-a-Chip Reveals the Contribution of the Presynaptic Compartment to Huntington's Disease.Virlogeux A, Moutaux E, Christaller W, Genoux A, Bruyère J, Fino E, Charlot B, Cazorla M, Saudou F. Cell Rep. 2018 Jan 2;22(1):110-122.

Self-propelling vesicles define glycolysis as the minimal energy machinery for neuronal transport. Hinckelmann MV, Virlogeux A, Niehage C, Poujol C, Choquet D, Hoflack B, Zala D, Saudou F. Nat Commun. 2016 Oct 24;7:13233.

The Biology of Huntingtin. Saudou F, Humbert S. Neuron. 2016 Mar 2;89(5):910-26.

Huntingtin proteolysis releases non-polyQ fragments that cause toxicity through dynamin 1 dysregulation. El-Daher MT, Hangen E, Bruyère J, Poizat G, Al-Ramahi I, Pardo R, Bourg N, Souquere S, Mayet C, Pierron G, Lévêque-Fort S, Botas J, Humbert S, Saudou F. EMBO J. 2015 Sep 2;34(17):2255-71.13.

Releasing the brake: restoring fast axonal transport in neurodegenerative disorders. Hinckelmann MV, Zala D, Saudou F. Trends Cell Biol. 2013 Dec;23(12):634-43.

Mutant Huntingtin alters retrograde transport of TrkB receptors in striatal dendrites. Liot G, Zala D, Pla P, Mottet G, Piel M, Saudou F. J Neurosci. 2013 Apr 10;33(15):6298-309.

Huntingtin acts non cell-autonomously on hippocampal neurogenesis and controls anxiety-related behaviors in adult mouse.Pla P, Orvoen S, Benstaali C, Dodier S, Gardier AM, David DJ, Humbert S, Saudou F. PLoS One. 2013 Sep 3;8(9):e73902.

Vesicular glycolysis provides on-board energy for fast axonal transport. Zala D, Hinckelmann MV, Yu H, Lyra da Cunha MM, Liot G, Cordelières FP, Marco S, Saudou F. Cell. 2013 Jan 31;152(3):479-91.

Huntingtin's function in axonal transport is conserved in Drosophila melanogaster. Zala D, Hinckelmann MV, Saudou F. PLoS One. 2013;8(3):e60162.

Ciliogenesis is regulated by a huntingtin-HAP1-PCM1 pathway and is altered in Huntington disease. Keryer G, Pineda JR, Liot G, Kim J, Dietrich P, Benstaali C, Smith K, Cordelières FP, Spassky N, Ferrante RJ, Dragatsis I, Saudou F. J Clin Invest. 2011 Nov;121(11):4372-82.


 

 


Updated on February 24, 2020
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