Bio

Professional Education


  • Doctorat, Universite De Bordeaux Ii (2008)
  • Master of Science, Universite De Bordeaux Ii (2006)
  • License, Universite De Bordeaux I (2003)
  • Maitrise, Universite De Bordeaux Ii (2005)

Stanford Advisors


Publications

Journal Articles


  • Exome sequencing to identify de novo mutations in sporadic ALS trios. Nature neuroscience Chesi, A., Staahl, B. T., Jovicic, A., Couthouis, J., Fasolino, M., Raphael, A. R., Yamazaki, T., Elias, L., Polak, M., Kelly, C., Williams, K. L., Fifita, J. A., Maragakis, N. J., Nicholson, G. A., King, O. D., Reed, R., Crabtree, G. R., Blair, I. P., Glass, J. D., Gitler, A. D. 2013; 16 (7): 851-855

    Abstract

    Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease whose causes are still poorly understood. To identify additional genetic risk factors, we assessed the role of de novo mutations in ALS by sequencing the exomes of 47 ALS patients and both of their unaffected parents (n = 141 exomes). We found that amino acid-altering de novo mutations were enriched in genes encoding chromatin regulators, including the neuronal chromatin remodeling complex (nBAF) component SS18L1 (also known as CREST). CREST mutations inhibited activity-dependent neurite outgrowth in primary neurons, and CREST associated with the ALS protein FUS. These findings expand our understanding of the ALS genetic landscape and provide a resource for future studies into the pathogenic mechanisms contributing to sporadic ALS.

    View details for DOI 10.1038/nn.3412

    View details for PubMedID 23708140

  • Evaluating the role of the FUS/TLS-related gene EWSR1 in amyotrophic lateral sclerosis HUMAN MOLECULAR GENETICS Couthouis, J., Hart, M. P., Erion, R., King, O. D., Diaz, Z., Nakaya, T., Ibrahim, F., Kim, H., Mojsilovic-Petrovic, J., Panossian, S., Kim, C. E., Frackelton, E. C., Solski, J. A., Williams, K. L., Clay-Falcone, D., Elman, L., McCluskey, L., Greene, R., Hakonarson, H., Kalb, R. G., Lee, V. M., Trojanowski, J. Q., Nicholson, G. A., Blair, I. P., Bonini, N. M., Van Deerlin, V. M., Mourelatos, Z., Shorter, J., Gitler, A. D. 2012; 21 (13): 2899-2911

    Abstract

    Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting motor neurons. Mutations in related RNA-binding proteins TDP-43, FUS/TLS and TAF15 have been connected to ALS. These three proteins share several features, including the presence of a bioinformatics-predicted prion domain, aggregation-prone nature in vitro and in vivo and toxic effects when expressed in multiple model systems. Given these commonalities, we hypothesized that a related protein, EWSR1 (Ewing sarcoma breakpoint region 1), might also exhibit similar properties and therefore could contribute to disease. Here, we report an analysis of EWSR1 in multiple functional assays, including mutational screening in ALS patients and controls. We identified three missense variants in EWSR1 in ALS patients, which were absent in a large number of healthy control individuals. We show that disease-specific variants affect EWSR1 localization in motor neurons. We also provide multiple independent lines of in vitro and in vivo evidence that EWSR1 has similar properties as TDP-43, FUS and TAF15, including aggregation-prone behavior in vitro and ability to confer neurodegeneration in Drosophila. Postmortem analysis of sporadic ALS cases also revealed cytoplasmic mislocalization of EWSR1. Together, our studies highlight a potential role for EWSR1 in ALS, provide a collection of functional assays to be used to assess roles of additional RNA-binding proteins in disease and support an emerging concept that a class of aggregation-prone RNA-binding proteins might contribute broadly to ALS and related neurodegenerative diseases.

    View details for DOI 10.1093/hmg/dds116

    View details for Web of Science ID 000305457700006

    View details for PubMedID 22454397

  • A yeast functional screen predicts new candidate ALS disease genes PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Couthouis, J., Hart, M. P., Shorter, J., DeJesus-Hernandez, M., Erion, R., Oristano, R., Liu, A. X., Ramos, D., Jethava, N., Hosangadi, D., Epstein, J., Chiang, A., Diaz, Z., Nakaya, T., Ibrahim, F., Kim, H., Solski, J. A., Williams, K. L., Mojsilovic-Petrovic, J., Ingre, C., Boylan, K., Graff-Radford, N. R., Dickson, D. W., Clay-Falcone, D., Elman, L., McCluskey, L., Greene, R., Kalb, R. G., Lee, V. M., Trojanowski, J. Q., Ludolph, A., Robberecht, W., Andersen, P. M., Nicholson, G. A., Blair, I. P., King, O. D., Bonini, N. M., Van Deerlin, V., Rademakers, R., Mourelatos, Z., Gitler, A. D. 2011; 108 (52): 20881-20890

    Abstract

    Amyotrophic lateral sclerosis (ALS) is a devastating and universally fatal neurodegenerative disease. Mutations in two related RNA-binding proteins, TDP-43 and FUS, that harbor prion-like domains, cause some forms of ALS. There are at least 213 human proteins harboring RNA recognition motifs, including FUS and TDP-43, raising the possibility that additional RNA-binding proteins might contribute to ALS pathogenesis. We performed a systematic survey of these proteins to find additional candidates similar to TDP-43 and FUS, followed by bioinformatics to predict prion-like domains in a subset of them. We sequenced one of these genes, TAF15, in patients with ALS and identified missense variants, which were absent in a large number of healthy controls. These disease-associated variants of TAF15 caused formation of cytoplasmic foci when expressed in primary cultures of spinal cord neurons. Very similar to TDP-43 and FUS, TAF15 aggregated in vitro and conferred neurodegeneration in Drosophila, with the ALS-linked variants having a more severe effect than wild type. Immunohistochemistry of postmortem spinal cord tissue revealed mislocalization of TAF15 in motor neurons of patients with ALS. We propose that aggregation-prone RNA-binding proteins might contribute very broadly to ALS pathogenesis and the genes identified in our yeast functional screen, coupled with prion-like domain prediction analysis, now provide a powerful resource to facilitate ALS disease gene discovery.

    View details for DOI 10.1073/pnas.1109434108

    View details for Web of Science ID 000298479900012

    View details for PubMedID 22065782

  • The toxicity of an "artificial" amyloid is related to how it interacts with membranes PRION Couthouis, J., Marchal, C., D'Angelo, F., Berthelot, K., Cullin, C. 2010; 4 (4): 283-291

    Abstract

    Despite intensive research into how amyloid structures can impair cellular viability, the molecular nature of these toxic species and the cellular mechanisms involved are not clearly defined and may differ from one disease to another. We systematically analyzed, in Saccharomyces cerevisiae, genes that increase the toxicity of an amyloid (M8), previously selected in yeast on the sole basis of its cellular toxicity (and consequently qualified as "artificial"). This genomic screening identified the Vps-C HOPS (homotypic vacuole fusion and protein sorting) complex as a key-player in amyloid toxicity. This finding led us to analyze further the phenotype induced by M8 expression. M8-expressing cells displayed an identical phenotype to vps mutants in terms of endocytosis, vacuolar morphology and salt sensitivity. The direct and specific interaction between M8 and lipids reinforces the role of membrane formation in toxicity due to M8. Together these findings suggest a model in which amyloid toxicity results from membrane fission.

    View details for DOI 10.4161/pri.4.4.13126

    View details for Web of Science ID 000285872900007

    View details for PubMedID 21057225

  • Screening for Toxic Amyloid in Yeast Exemplifies the Role of Alternative Pathway Responsible for Cytotoxicity PLOS ONE Couthouis, J., Rebora, K., Immel, F., Berthelot, K., Castroviejo, M., Cullin, C. 2009; 4 (3)

    Abstract

    The relationship between amyloid and toxic species is a central problem since the discovery of amyloid structures in different diseases. Despite intensive efforts in the field, the deleterious species remains unknown at the molecular level. This may reflect the lack of any structure-toxicity study based on a genetic approach. Here we show that a structure-toxicity study without any biochemical prerequisite can be successfully achieved in yeast. A PCR mutagenesis of the amyloid domain of HET-s leads to the identification of a mutant that might impair cellular viability. Cellular and biochemical analyses demonstrate that this toxic mutant forms GFP-amyloid aggregates that differ from the wild-type aggregates in their shape, size and molecular organization. The chaperone Hsp104 that helps to disassemble protein aggregates is strictly required for the cellular toxicity. Our structure-toxicity study suggests that the smallest aggregates are the most toxic, and opens a new way to analyze the relationship between structure and toxicity of amyloid species.

    View details for DOI 10.1371/journal.pone.0004539

    View details for Web of Science ID 000265490600001

    View details for PubMedID 19262694

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