Luc Dupuis

Publications (57) View all

• Article: Investigating the contribution of VAPB/ALS8 loss of function in amyotrophic lateral sclerosis.

  Edor Kabashi, Hajer El Oussini, Valérie Bercier, François Gros-Louis, Paul N Valdmanis, Jonathan McDearmid, Inge A Mejier, Patrick A Dion, Nicolas Dupre, David Hollinger, Jérome Sinniger, Sylvie Dirrig-Grosch, William Camu, Vincent Meininger, Jean-Philippe Loeffler, Frédérique René, Pierre Drapeau, Guy A Rouleau, Luc Dupuis
  [show abstract] [hide abstract]
  ABSTRACT: The mutations P56S and T46I in the gene encoding vesicle-associated membrane protein-associated protein B/C (VAPB) cause ALS8, a familial form of amyotrophic lateral sclerosis (ALS). Overexpression of mutant forms of VAPB leads to cytosolic aggregates, suggesting a gain of function of the mutant protein. However, recent work suggested that the loss of VAPB function could be the major mechanism leading to ALS8. Here, we used multiple genetic and experimental approaches to study whether VAPB loss of function might be sufficient to trigger motor neuron degeneration. In order to identify additional ALS-associated VAPB mutations, we screened the entire VAPB gene in a cohort of ALS patients and detected two mutations (A145V and S160Δ). To directly address the contribution of VAPB loss of function in ALS, we generated zebrafish and mouse models with either a decreased or a complete loss of Vapb expression. Vapb knockdown in zebrafish led to swimming deficits. Mice knocked-out for Vapb showed mild motor deficits after 18 months of age yet had innervated neuromuscular junctions (NMJs). Importantly, overexpression of VAPB mutations were unable to rescue the motor deficit caused by Vapb knockdown in zebrafish and failed to cause a toxic gain-of-function defect on their own. Thus, Vapb loss of function weakens the motor system of vertebrate animal models but is on its own unable to lead to a complete ALS phenotype. Our findings are consistent with the notion that VAPB mutations constitute a risk factor for motor neuron disease through a loss of VAPB function.
  Human Molecular Genetics 03/2013; · 7.64 Impact Factor
• Source

  Available from: Dominique Bonnefont-Rousselot

  Dataset: Pradat et al. Amyotr Lat Scler 2010

  Pierre-Francois Pradat, Gaelle Bruneteau, Paul H Gordon, Luc Dupuis, Dominique Bonnefont-Rousselot, Dominique Simon, Francois Salachas, Philippe Corcia, Vincent Frochot, Jean-Marc Lacorte, Claude Jardel, Christiane Coussieu, Nadine Le Forestier, Lucette Lacomblez, Jean-Philippe Loeffler, Vincent Meininger
• Source

  Available from: Beatrice Lannes

  Article: Degeneration of serotonergic neurons in amyotrophic lateral sclerosis: a link to spasticity.

  Christel Dentel, Lavinia Palamiuc, Alexandre Henriques, Béatrice Lannes, Odile Spreux-Varoquaux, Lise Gutknecht, Frédérique René, Andoni Echaniz-Laguna, Jose-Luis Gonzalez de Aguilar, Klaus Peter Lesch, Vincent Meininger, Jean-Philippe Loeffler, Luc Dupuis
  [show abstract] [hide abstract]
  ABSTRACT: Spasticity is a common and disabling symptom observed in patients with central nervous system diseases, including amyotrophic lateral sclerosis, a disease affecting both upper and lower motor neurons. In amyotrophic lateral sclerosis, spasticity is traditionally thought to be the result of degeneration of the upper motor neurons in the cerebral cortex, although degeneration of other neuronal types, in particular serotonergic neurons, might also represent a cause of spasticity. We performed a pathology study in seven patients with amyotrophic lateral sclerosis and six control subjects and observed that central serotonergic neurons suffer from a degenerative process with prominent neuritic degeneration, and sometimes loss of cell bodies in patients with amyotrophic lateral sclerosis. Moreover, distal serotonergic projections to spinal cord motor neurons and hippocampus systematically degenerated in patients with amyotrophic lateral sclerosis. In SOD1 (G86R) mice, a transgenic model of amyotrophic lateral sclerosis, serotonin levels were decreased in brainstem and spinal cord before onset of motor symptoms. Furthermore, there was noticeable atrophy of serotonin neuronal cell bodies along with neuritic degeneration at disease onset. We hypothesized that degeneration of serotonergic neurons could underlie spasticity in amyotrophic lateral sclerosis and investigated this hypothesis in vivo using tail muscle spastic-like contractions in response to mechanical stimulation as a measure of spasticity. In SOD1 (G86R) mice, tail muscle spastic-like contractions were observed at end-stage. Importantly, they were abolished by 5-hydroxytryptamine-2b/c receptors inverse agonists. In line with this, 5-hydroxytryptamine-2b receptor expression was strongly increased at disease onset. In all, we show that serotonergic neurons degenerate during amyotrophic lateral sclerosis, and that this might underlie spasticity in mice. Further research is needed to determine whether inverse agonists of 5-hydroxytryptamine-2b/c receptors could be of interest in treating spasticity in patients with amyotrophic lateral sclerosis.
  Brain 10/2012; · 9.46 Impact Factor
• Article: BBS-Induced Ciliary Defect Enhances Adipogenesis, Causing Paradoxical Higher-Insulin Sensitivity, Glucose Usage, and Decreased Inflammatory Response.

  Vincent Marion, Anaïs Mockel, Charlie De Melo, Cathy Obringer, Aurélie Claussmann, Alban Simon, Nadia Messaddeq, Myriam Durand, Luc Dupuis, Jean-Philippe Loeffler, Peter King, Catherine Mutter-Schmidt, Nikolai Petrovsky, Corinne Stoetzel, Hélène Dollfus
  [show abstract] [hide abstract]
  ABSTRACT: Studying ciliopathies, like the Bardet-Biedl syndrome (BBS), allow the identification of signaling pathways potentially involved in common diseases, sharing phenotypic features like obesity or type 2 diabetes. Given the close association between obesity and insulin resistance, obese BBS patients would be expected to be insulin resistant. Surprisingly, we found that a majority of obese BBS patients retained normal glucose tolerance and insulin sensitivity. Patient's adipose tissue biopsies revealed upregulation of adipogenic genes and decrease of inflammatory mediators. In vitro studies on human primary mesenchymal stem cells (MSCs) showed that BBS12 inactivation facilitated adipogenesis, increased insulin sensitivity, and glucose utilization. We generated a Bbs12(-/-) mouse model to assess the impact of Bbs12 inactivation on adipocyte biology. Despite increased obesity, glucose tolerance was increased with specific enhanced insulin sensitivity in the fat. This correlated with an active recruitment of MSCs resulting in adipose tissue hyperplasia and decreased in inflammation.
  Cell metabolism 09/2012; 16(3):363-77. · 17.35 Impact Factor
• Article: Progranulin bridges energy homeostasis and fronto-temporal dementia.

  Luc Dupuis, Asa Petersen, Patrick Weydt
  Cell metabolism 03/2012; 15(3):269-70; author reply 270. · 17.35 Impact Factor