Frédéric Saudou

Université Paris-Sud 11, Orsay, Île-de-France, France

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Publications (80)628.96 Total impact

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    ABSTRACT: Huntington's disease (HD) is an autosomal dominant disease caused by an expansion of CAG repeats in the gene encoding for huntingtin. Brain metabolic dysfunction and altered Akt signaling pathways have been associated with disease progression. Nevertheless, conflicting results persist regarding the role of insulin-like growth factor-1 (IGF-1)/Akt pathway in HD. While high plasma levels of IGF-1 correlated with cognitive decline in HD patients, other data showed protective effects of IGF-1 in HD striatal neurons and R6/2 mice. Thus, in the present study, we investigated motor phenotype, peripheral and central metabolic profile, and striatal and cortical signaling pathways in YAC128 mice subjected to intranasal administration of recombinant human IGF-1 (rhIGF-1) for 2 weeks, in order to promote IGF-1 delivery to the brain. We show that IGF-1 supplementation enhances IGF-1 cortical levels and improves motor activity and both peripheral and central metabolic abnormalities in YAC128 mice. Moreover, decreased Akt activation in HD mice brain was ameliorated following IGF-1 administration. Upregulation of Akt following rhIGF-1 treatment occurred concomitantly with increased phosphorylation of mutant huntingtin on Ser421. These data suggest that intranasal administration of rhIGF-1 ameliorates HD-associated glucose metabolic brain abnormalities and mice phenotype.
    Molecular Neurobiology 12/2013; · 5.47 Impact Factor
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    ABSTRACT: Emerging evidence suggests that the dysregulation of fast axonal transport (FAT) plays a crucial role in several neurodegenerative disorders. Some of these diseases are caused by mutations affecting the molecular motors or adaptors that mediate FAT, and transport defects in organelles such as mitochondria and vesicles are observed in most, if not all neurodegenerative disorders. The relationship between neurodegenerative disorders and FAT is probably due to the extreme polarization of neurons, which extend long processes such as axons and dendrites. These characteristics render neurons particularly sensitive to transport alterations. Here we review the impact of such alterations on neuronal survival. We also discuss various strategies that might restore FAT, potentially slowing disease progression.
    Trends in cell biology 09/2013; · 12.12 Impact Factor
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    ABSTRACT: Huntington disease (HD) is associated with early psychiatric symptoms including anxiety and depression. Here, we demonstrate that wild-type huntingtin, the protein mutated in HD, modulates anxiety/depression-related behaviors according to its phosphorylation at serines 1181 and 1201. Genetic phospho-ablation at serines 1181 and 1201 in mouse reduces basal levels of anxiety/depression-like behaviors. We observe that the reduction in anxiety/depression-like phenotypes is associated with increased adult hippocampal neurogenesis. By improving the attachment of molecular motors to microtubules, huntingtin dephosphorylation increases axonal transport of BDNF, a crucial factor for hippocampal adult neurogenesis. Consequently, the huntingtin-mediated increased BDNF dynamics lead to an increased delivery and signaling of hippocampal BDNF. These results support the notion that huntingtin participates in anxiety and depression-like behavior and is thus relevant to the etiology of mood disorders and anxiety/depression in HD.
    Journal of Neuroscience 05/2013; 33(20):8608-20. · 6.91 Impact Factor
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    ABSTRACT: Huntingtin (HTT), the protein mutated in Huntington's disease (HD), controls transport of the neurotrophin, brain-derived neurotrophic factor (BDNF), within corticostriatal neurons. Transport and delivery of BDNF to the striatum are reduced in disease, which contributes to striatal neuron degeneration. BDNF released by cortical neurons activates TrkB receptors at striatal dendrites to promote striatum survival. However, it remains to be determined whether transport of TrkB, the BDNF receptor, depends on HTT and whether such transport is altered in mutant situation. Here we show that TrkB binds to and colocalizes with HTT and dynein. Silencing HTT reduces vesicular transport of TrkB in striatal neurons. In HD, the polyQ expansion in HTT alters the binding of TrkB-containing vesicles to microtubules and reduces transport. Using a combination of microfluidic devices that isolate dendrites from cell bodies and BDNF coupled to quantum dots, we selectively analyzed TrkB retrograde transport in response to BDNF stimulation at dendrite terminals. We show that the retrograde transport of TrkB vesicles within striatal dendrites and the BDNF/TrkB-induced signaling through ERK phosphorylation and c-fos induction are decreased in neurons from an HD mouse model. Together, our findings demonstrate that HTT is a crucial regulator of TrkB trafficking. Transport defects in HD are not restricted to BDNF transport in cortical neurons but also affect trafficking of its ligand-bound receptor in the striatal neurons. This transport alteration may further impair BDNF-TrkB survival signaling within the corticostriatal connection that is most affected in HD.
    Journal of Neuroscience 04/2013; 33(15):6298-309. · 6.91 Impact Factor
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    ABSTRACT: Fast axonal transport (FAT) requires consistent energy over long distances to fuel the molecular motors that transport vesicles. We demonstrate that glycolysis provides ATP for the FAT of vesicles. Although inhibiting ATP production from mitochondria did not affect vesicles motility, pharmacological or genetic inhibition of the glycolytic enzyme GAPDH reduced transport in cultured neurons and in Drosophila larvae. GAPDH localizes on vesicles via a huntingtin-dependent mechanism and is transported on fast-moving vesicles within axons. Purified motile vesicles showed GAPDH enzymatic activity and produced ATP. Finally, we show that vesicular GAPDH is necessary and sufficient to provide on-board energy for fast vesicular transport. Although detaching GAPDH from vesicles reduced transport, targeting GAPDH to vesicles was sufficient to promote FAT in GAPDH deficient neurons. This specifically localized glycolytic machinery may supply constant energy, independent of mitochondria, for the processive movement of vesicles over long distances in axons. PAPERFLICK:
    Cell 01/2013; 152(3):479-91. · 31.96 Impact Factor
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    ABSTRACT: Huntington's disease (HD) is a fatal neurodegenerative disease, characterized by motor defects and psychiatric symptoms, including mood disorders such as anxiety and depression. HD is caused by an abnormal polyglutamine (polyQ) expansion in the huntingtin (HTT) protein. The development and analysis of various mouse models that express pathogenic polyQ-HTT revealed a link between mutant HTT and the development of anxio-depressive behaviors and various hippocampal neurogenesis defects. However, it is unclear whether such phenotype is linked to alteration of HTT wild-type function in adults. Here, we report the analysis of a new mouse model in which HTT is inducibly deleted from adult mature cortical and hippocampal neurons using the CreER(T2)/Lox system. These mice present defects in both the survival and the dendritic arborization of hippocampal newborn neurons. Our data suggest that these non-cell autonomous effects are linked to defects in both BDNF transport and release upon HTT silencing in hippocampal neurons, and in BDNF/TrkB signaling. The controlled deletion of HTT also had anxiogenic-like effects. Our results implicate endogenous wild-type HTT in adult hippocampal neurogenesis and in the control of mood disorders.
    PLoS ONE 01/2013; 8(9):e73902. · 3.73 Impact Factor
  • (In Revision). 01/2013;
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    ABSTRACT: Huntington's disease (HD) is a devastating dominantly inherited neurodegenerative disorder caused by an abnormal polyglutamine expansion in the N-terminal part of the huntingtin (HTT) protein. HTT is a large scaffold protein that interacts with more than a hundred proteins and is probably involved in several cellular functions. The mutation is dominant, and is thought to confer new and toxic functions to the protein. However, there is emerging evidence that the mutation also alters HTT's normal functions. Therefore, HD models need to recapitulate this duality if they are to be relevant. Drosophila melanogaster is a useful in vivo model, widely used to study HD through the overexpression of full-length or N-terminal fragments of mutant human HTT. However, it is unclear whether Drosophila huntingtin (DmHTT) shares functions similar to the mammalian HTT. Here, we used various complementary approaches to analyze the function of DmHTT in fast axonal transport. We show that DmHTT interacts with the molecular motor dynein, associates with vesicles and co-sediments with microtubules. DmHTT co-localizes with Brain-derived neurotrophic factor (BDNF)-containing vesicles in rat cortical neurons and partially replaces mammalian HTT in a fast axonal transport assay. DmHTT-KO flies show a reduced fast axonal transport of synaptotagmin vesicles in motoneurons in vivo. These results suggest that the function of HTT in axonal transport is conserved between flies and mammals. Our study therefore validates Drosophila melanogaster as a model to study HTT function, and its dysfunction associated with HD.
    PLoS ONE 01/2013; 8(3):e60162. · 3.73 Impact Factor
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    Frédéric Saudou
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    ABSTRACT: Cilia are unique cellular organelles found in nearly all cell types. In recent years, the importance of these organelles has been highlighted by the discovery that mutations in genes encoding proteins related to cilia biogenesis and function cause a class of complex syndromes termed ciliopathies. Emerging evidence suggests interactions among the various ciliopathy-associated proteins, but the precise mechanisms by which these interactions generate functional networks have remained elusive. In this issue of the JCI, Rachel and colleagues have now clearly linked two ciliopathy-associated proteins (CEP290 and MKKS). Surprisingly, the effects of a hypomorphic disease-causing Cep290 allele were rescued by loss of MKKS function, suggesting that it might be possible to treat some ciliopathies by fine-tuning interactions within the expanding ciliary network.
    The Journal of clinical investigation 03/2012; 122(4):1198-202. · 15.39 Impact Factor
  • Médecine/Science (Paris). 01/2012; Jan(28(1)):44-46.
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    Medecine sciences: M/S 01/2012; 28(1):44-6. · 0.56 Impact Factor
  • Médecine/Sciences (Paris). 01/2012;
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    ABSTRACT: Huntington's disease (HD) is a devastating genetic neurodegenerative disorder. Major depressive disorder and more generally mood disorders are a major component of the symptoms during the pre-motor symptomatic stages of the disease. We report here that knock-in Hdh(Q111) mice, an animal model of HD, that carry an expanded polyglutamine stretch in the mouse HD protein show an anxio-depressive-like phenotype prior to any impairment of the locomotor function. Strikingly, whereas females develop preferentially a depressive-like behaviour, males had an increased anxiety-like phenotype. Since adult hippocampal neurogenesis has been associated to the pathophysiology and treatment of depression, we investigated whether changes in behavioural phenotypes are associated with proliferation or maturation impairments. Whereas cell proliferation was not affected in knock-in Hdh(Q111) mice, a male-specific marked decrease in late maturation of newborn neurons was observed in the adult dentate gyrus. Together, our results highlight sex differences in both behaviour and adult neurogenesis in a knock-in model of HD.
    Neuroscience Letters 12/2011; 507(2):127-32. · 2.03 Impact Factor
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    ABSTRACT: Polyglutamine (polyQ) stretches exceeding a threshold length confer a toxic function to proteins that contain them and cause at least nine neurological disorders. The basis for this toxicity threshold is unclear. Although polyQ expansions render proteins prone to aggregate into inclusion bodies, this may be a neuronal coping response to more toxic forms of polyQ. The exact structure of these more toxic forms is unknown. Here we show that the monoclonal antibody 3B5H10 recognizes a species of polyQ protein in situ that strongly predicts neuronal death. The epitope selectively appears among some of the many low-molecular-weight conformational states assumed by expanded polyQ and disappears in higher-molecular-weight aggregated forms, such as inclusion bodies. These results suggest that protein monomers and possibly small oligomers containing expanded polyQ stretches can adopt a conformation that is recognized by 3B5H10 and is toxic or closely related to a toxic species.
    Nature Chemical Biology 12/2011; 7(12):925-34. · 12.95 Impact Factor
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    ABSTRACT: Mecp2 deficiency or overexpression causes a wide spectrum of neurological diseases in humans among which Rett Syndrome is the prototype. Pathogenic mechanisms are thought to involve transcriptional deregulation of target genes such as Bdnf together with defects in the general transcriptional program of affected cells. Here we found that two master genes, Huntingtin (Htt) and huntingtin-associated protein (Hap1), involved in the control of Bdnf axonal transport, are altered in the brain of Mecp2-deficient mice. We also revealed an in vivo defect of Bdnf transport throughout the cortico striatal pathway of Mecp2-deficient animals. We found that the velocity of Bdnf-containing vesicles is reduced in vitro in the Mecp2-deficient axons and this deficit can be rescued by the re-expression of Mecp2. The defect in axonal transport is not restricted to Bdnf since transport of the amyloid precursor protein (App) that is Htt and Hap1-dependent is also altered. Finally, treating Mecp2-deficient mice with cysteamine, a molecule increasing the secretion of Bdnf vesicles, improved the lifespan and reduced motor defects, suggesting a new therapeutic strategy for Rett syndrome.
    Neurobiology of Disease 11/2011; 45(2):786-95. · 5.62 Impact Factor
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    ABSTRACT: Huntington disease (HD) is a devastating autosomal-dominant neurodegenerative disorder. It is caused by expansion of a CAG repeat in the first exon of the huntingtin (HTT) gene that encodes a mutant HTT protein with a polyglutamine (polyQ) expansion at the amino terminus. Here, we demonstrate that WT HTT regulates ciliogenesis by interacting through huntingtin-associated protein 1 (HAP1) with pericentriolar material 1 protein (PCM1). Loss of Htt in mouse cells impaired the retrograde trafficking of PCM1 and thereby reduced primary cilia formation. In mice, deletion of Htt in ependymal cells led to PCM1 mislocalization, alteration of the cilia layer, and hydrocephalus. Pathogenic polyQ expansion led to centrosomal accumulation of PCM1 and abnormally long primary cilia in mouse striatal cells. PCM1 accumulation in ependymal cells was associated with longer cilia and disorganized cilia layers in a mouse model of HD and in HD patients. Longer cilia resulted in alteration of the cerebrospinal fluid flow. Thus, our data indicate that WT HTT is essential for protein trafficking to the centrosome and normal ciliogenesis. In HD, hypermorphic ciliogenesis may affect signaling and neuroblast migration so as to dysregulate brain homeostasis and exacerbate disease progression.
    The Journal of clinical investigation 11/2011; 121(11):4372-82. · 15.39 Impact Factor
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    ABSTRACT: Amyloid peptide (Aβ) is generated by sequential cleavage of the amyloid precursor protein (APP) by β-secretase (Bace1) and γ-secretase. Aβ production increases after plasma membrane cholesterol loading through unknown mechanisms. To determine how APP-Bace1 proximity affects this phenomenon, we developed a fluorescence lifetime imaging microscopy-Förster resonance energy transfer (FLIM-FRET) technique for visualization of these molecules either by epifluorescence or at the plasma membrane only using total internal reflection fluorescence. Further, we used fluorescence correlation spectroscopy to determine the lipid rafts partition of APP-yellow fluorescent protein (YFP) and Bace1-green fluorescent protein (GFP) molecules at the plasma membrane of neurons. We show that less than 10 min after cholesterol exposure, Bace1-GFP/APP-mCherry proximity increases selectively at the membrane and APP relocalizes to raft domains, preceded by rapid endocytosis. After longer cholesterol exposures, APP and Bace1 are found in proximity intracellularly. We demonstrate that cholesterol loading does not increase Aβ production by having a direct impact on Bace1 catalytic activity but rather by altering the accessibility of Bace1 to its substrate, APP. This change in accessibility is mediated by clustering in lipid rafts, followed by rapid endocytosis.
    The FASEB Journal 01/2011; 25(4):1295-305. · 5.70 Impact Factor
  • Alzheimers & Dementia - ALZHEIMERS DEMENT. 01/2011; 7(4).
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    ABSTRACT: Recent findings suggest that altered cholesterol homeostasis may contribute to the pathophysiology of Huntington's disease (HD). To understand the underlying mechanisms, here we used a combination of two-photon microscopy, epifluorescence, and biochemical methods to visualize and quantify lipid distribution in cell cultures expressing mutant huntingtin. Such expression promotes lipid imbalance, and cholesterol accumulation in cellular and murine models and in HD-affected human brains. Interestingly, cells expressing mutant huntingtin also showed higher content of ordered domains in their plasma membranes. These findings correlated with high levels of caveolin-1 and glycosphingolipid GM1, two well-defined markers of cholesterol-enriched domains, at the cell surface. In addition, cells expressing mutant huntingtin showed increased localization of NMDA receptors with cholesterol-enriched domains, contributing to increased NMDA receptor susceptibility to excitotoxic insults. Treatment with simvastatin or β-cyclodextrin, two cholesterol-lowering drugs, reduced the content of ordered domains at the cell surface, which in turn, protected cells against NMDA-mediated excitotoxicity. Taken together, our results indicate that mutant huntingtin produces accumulation of cholesterol and alters its cellular distribution that contributes to NMDA-mediated excitotoxicity. Administration of drugs that recover this effect, such as simvastatin could be beneficial for the treatment of HD.
    Journal of Neurochemistry 10/2010; 115(1):153-67. · 3.97 Impact Factor
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    ABSTRACT: Huntingtin is the protein mutated in Huntington's disease, a devastating neurodegenerative disorder. We demonstrate here that huntingtin is essential to control mitosis. Huntingtin is localized at spindle poles during mitosis. RNAi-mediated silencing of huntingtin in cells disrupts spindle orientation by mislocalizing the p150(Glued) subunit of dynactin, dynein, and the large nuclear mitotic apparatus NuMA protein. This leads to increased apoptosis following mitosis of adherent cells in vitro. In vivo inactivation of huntingtin by RNAi or by ablation of the Hdh gene affects spindle orientation and cell fate of cortical progenitors of the ventricular zone in mouse embryos. This function is conserved in Drosophila, the specific disruption of Drosophila huntingtin in neuroblast precursors leading to spindle misorientation. Moreover, Drosophila huntingtin restores spindle misorientation in mammalian cells. These findings reveal an unexpected role for huntingtin in dividing cells, with potential important implications in health and disease.
    Neuron 08/2010; 67(3):392-406. · 15.77 Impact Factor

Publication Stats

5k Citations
734 Downloads
628.96 Total Impact Points

Institutions

  • 2009–2013
    • Université Paris-Sud 11
      Orsay, Île-de-France, France
  • 2003–2013
    • French National Centre for Scientific Research
      Lutetia Parisorum, Île-de-France, France
  • 2002–2013
    • Institut Curie
      Lutetia Parisorum, Île-de-France, France
  • 1998
    • Harvard Medical School
      • Department of Neurology
      Boston, MA, United States
  • 1996–1998
    • Columbia University
      • Center for Neurobiology and Behavior
      New York City, NY, United States
  • 1996–1997
    • Institut de Génétique et de Biologie Moléculaire et Cellulaire
      Strasburg, Alsace, France
  • 1992
    • French Institute of Health and Medical Research
      Lutetia Parisorum, Île-de-France, France