Description: Macintosh HD:Users:couthouis:Desktop:image001.jpgJulien Couthouis, Ph.D.

279 Campus Dr. - B275, Beckman Bldg Stanford, CA 94305-5120
Lab Phone: +1 (650) 725-3646
E-Mail:

Personal Information

Country of citizenship: France

Current US visa status: H1B

Research Experience and Skills

During my Ph.D. I studied prion mechanisms and amyloids toxicity in yeast. This allowed me to get an extensive experience in molecular biology, mutagenesis, genetic screens, drug screens and phenotypic characterizations using microscopy and cell culture.

I used this knowledge during in my postdoctoral work to while studying the genetics of ALS and other neurodegenerative, neuromuscular and neurological diseases. The use of next generation sequencing coupled with the power of yeast genetics allowed me to successfully identify new genes and risk factors in these diseases. While my original genetics background was mostly in yeast, I successfully set up and ran the NGS platform in my postdoc lab, from DNA extraction, library preparation and set up of the bioinformatics tools used for data analysis.

 

Degrees and Diplomas

2008                            Ph. D. in Genetics

Bordeaux II University, Bordeaux, France

 

2005                            Master in Cellular Biology and Physiology

Bordeaux II University, Bordeaux, France

 

2003                            License in Cellular Biology and Physiology

Bordeaux I University, Talence, France

 

2002                            BCPST Preparatory class – ENS admissibility L2 equivalency.

Lycée Michel Montaigne, Bordeaux, France

Past and Current Research Projects

2010-2011                     University of Pennsylvania, Philadelphia, PA, USA                        Postdoctoral

2012-2014                     Stanford University, Stanford, CA, USA                           Postdoctoral

2015-Present                  Stanford University, Stanford, CA, USA                           Research Associate

                                   Advisor: Aaron D. GITLER, Ph.D., Associate Professor
 - Department of Genetics

Project: New ALS and FTLD disease genes.

Results: Based on the properties of TDP-43 and FUS/TLS, both known ALS related genes, an innovative yeast functional screen was designed to identify new human genes associated with the pathogenesis of ALS. Sequence analysis of two of these candidate genes, EWSR1 and TAF15, in sporadic ALS patients and controls identified two pathogenic variants for each gene. Functional studies provided evidence that EWSR1 and TAF15 have similar in vitro and in vivo properties as TDP-43 and FUS. They can confer neurodegeneration in Drosophila and their disease-associated variants affect localization of each respective protein in motor neurons. Postmortem analysis of sporadic ALS cases revealed cytoplasmic mislocalization of EWSR1 and TAF15.

Parallel projects using either high throughput sequencing of ALS trios, or using a custom library of candidate genes to sequence hundreds of sporadic ALS cases, identified novel variants responsible for ALS. These results are being followed up and confirmed by functional studies.

 

2005-2008                     CNRS - Bordeaux II University, Bordeaux, France                           Ph.D. Research

2008-2009                     CNRS - Bordeaux II University, Bordeaux, France                           Postdoctoral

                                   Advisor: Christophe CULLIN, Ph.D., Professeur UBS

Project: Study of amyloid toxicity in yeast using the P. anserina Het-s protein as model.

Results: Able to show that a harmless amyloid could be changed into a toxic one by cis or trans mutations. These mutants generate smaller amyloid species that seem to be the toxic ones. Moreover amyloid toxicity seems to be correlated with lipid interaction, especially vacuolar and endosomal structures.


 

Publications

1.     Cirulli ET*, Lasseigne BN*, Petrovski S, Sapp PC, Dion PA, Leblond CS, Couthouis J, Lu YF, Wang Q, Krueger BJ, Ren Z, Keebler J, Han Y, Levy SE, Boone BE, Wimbish JR, Waite LL, Jones AL, Carulli JP, Day-Williams AG, Staropoli JF, Xin WW, Chesi A, Raphael AR, McKenna-Yasek D, Cady J, Vianney de Jong JM, Kenna KP, Smith BN, Topp S, Miller J, Gkazi A; FALS Sequencing Consortium, Al-Chalabi A, van den Berg LH, Veldink J, Silani V, Ticozzi N, Shaw CE, Baloh RH, Appel S, Simpson E, Lagier-Tourenne C, Pulst SM, Gibson S, Trojanowski JQ, Elman L, McCluskey L, Grossman M, Shneider NA, Chung WK, Ravits JM, Glass JD, Sims KB, Van Deerlin VM, Maniatis T, Hayes SD, Ordureau A, Swarup S, Landers J, Baas F, Allen AS, Bedlack RS, Harper JW, Gitler AD, Rouleau GA, Brown R, Harms MB, Cooper GM, Harris T, Myers RM, Goldstein DB. Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways. Science, 2015 Feb 19. pii: aaa3650.

doi: 10.1126/science.aaa3650                                                                                                           PMID: 25700176

* Contributed equally

 

2.     Couthouis J*, Raphael AR*, Daneshjou R, Gitler AD. Targeted exon capture and sequencing in sporadic amyotrophic lateral sclerosis. PLoS Genet., 2014 Oct 9;10(10):e1004704.

doi: 10.1371/journal.pgen.1004704                                                                                                  PMID: 25299611

* Contributed equally

 

3.     Raphael AR*, Couthouis J*, Sakamuri S, Siskind C, Vogel H, Day JW, Gitler AD. Congenital muscular dystrophy and generalized epilepsy caused by GMPPB mutations. Brain Res., 2014 Aug 5;1575:66-71.

doi: 10.1016/j.brainres.2014.04.028                                                                                                 PMID: 24780531

* Contributed equally

 

4.     Couthouis J*, Raphael AR*, Siskind C*, Findlay AR, Buenrostro JD, Greenleaf WJ, Vogel H, Day JW, Flanigan KM, Gitler AD. Exome sequencing identifies a DNAJB6 mutation in a family with dominantly-inherited limb-girdle muscular dystrophy. Neuromuscul Disord., 2014 May;24(5):431-5.

doi: 10.1016/j.nmd.2014.01.014                                                                                                      PMID: 24594375

* Contributed equally

 

5.     Chesi A, Staahl BT, Jovičić A, Couthouis J, Fasolino M, Raphael AR, Yamazaki T, Elias L, Polak M, Kelly C, Williams KL, Fifita JA, Maragakis NJ, Nicholson GA, King OD, Reed R, Crabtree GR, Blair IP, Glass JD, Gitler AD. Exome sequencing to identify de novo mutations in sporadic ALS trios. Nat Neurosci., 2013 Jul;16(7):851-5

doi: 10.1038/nn.3412                                                                                                                                PMID: 23708140

6.     Couthouis J, Hart MP, Erion R, King OD, Diaz Z, Nakaya T, Ibrahim F, Kim HJ, Mojsilovic-Petrovic J, Panossian S, Kim CE, Frackelton EC, Solski JA, Williams KL, Clay-Falcone D, Elman L, McCluskey L, Greene R, Hakonarson H, Kalb RG, Lee VM, Trojanowski JQ, Nicholson GA, Blair IP, Bonini NM, Van Deerlin VM, Mourelatos Z, Shorter J, Gitler AD. Evaluating the role of the FUS/TLS-related gene EWSR1 in amyotrophic lateral sclerosis. Hum. Mol. Genet., 2012. Jul 1;21(13):2899-911.

doi: 10.1093/hmg/dds116 PMID: 22454397

 

7.     Couthouis J*, Hart M.P*, Shorter J*, DeJesus-Hernandez M, Erion R, Oristano R.E, Liu X.A, Ramos D, Jethava N, Hosangadi D, Epstein J, Chiang A, Diaz Z, Nakaya T, Ibrahim F, Kim H-J, Solski J.A, Williams K.L, Mojsilovic-Petrovic J, Ingre C, Boylan K, Graff-Radford N, Dickson D, Clay-Falcone D, Elman L, McCluskey L, Greene R, Kalb R.G, Lee V.M.Y, Trojanowski J.Q, Ludolph A.C, Robberecht W, Andersen P.M, Nicholson G.A, Blair I.P, King O.D, Bonini N.M, Van Deerlin V.M, Rademakers R, Mourelatos Z and Gitler A.D. A yeast functional screen predicts new candidate ALS disease genes. Proc Natl Acad Sci USA, 2011. 108(52): 20881-90.

doi: 10.1073/pnas.1109434108                                                                                                        PMID: 22065782

* Contributed equally

 

8.     Couthouis J*, Marchal C*, D’Angelo F, Berthelot K and Cullin C. The toxicity of an “artificial” amyloid is related to how it interacts with membranes. Prion, 2010. 4(4): 283-291.

doi: 10.4161/pri.4.4.13126                                                                                                             PMID: 21057225

* Contributed equally

 

9.     Couthouis J*, Rébora K*, Immel F, Berthelot K, Castroviejo M, Cullin C. Screening for toxic amyloid in yeast exemplifies the role of alternative pathway responsible for cytotoxicity. PLoS ONE, 2009. 4(3): e4539.

doi: 10.1371/journal.pone.0004539                                                                                                  PMID: 19262694

* Contributed equally


 

Mentoring and Teaching Experience

During both my Ph.D. and my postdoc I mentored students, from the high school through graduate level, helping them with their lab work, written reports and oral presentations for classes.

My teaching experience consisted of small group student classes focused on lab techniques (Yeast model, Genetics and molecular biology, Applications of NGS sequencing for the neurosciences).

Honors and Talks

2015                 Teaser talk and poster presentation: Stress Proteins in Growth, Development & Disease, Gordon Research Conference, Lucca, Italy.

2015                 Invited talk “ALS genetics: from misfolded RNA-binding proteins to the identification of new risk genes”: China ALS symposium, Beijing, China.

2014                 Poster presentation: 25th International Symposium on ALS/MND, Brussels, Belgium

2014                 Poster presentation: Stanford Genetics annual retreat, Monterey, CA

2014                 Poster presentation: Bay Area Aging Meeting, Stanford, CA.

2013                 Poster presentation: 8th Brain Research Conference, San Diego, CA

2013                 Poster presentation: Stanford Genetics annual retreat, Monterey, CA

2013                 Bay Area Aging Meeting Talk: RNA-binding proteins with prion domains in normal biology, aging, and disease. Novato, CA.

2012                 Poster presentation: Stanford Genetics annual retreat, Monterey, CA

2012                 Poster presentation: 25th Annual AFAR Grantee Conference, Santa Barbara, CA

2010                 Poster presentation: 11th annual Robert Packard Center for ALS Research Symposium, Baltimore, MA

2009                 Poster presentation: Cold Spring Harbor Laboratory Meeting, Cold Spring Harbor, NY

2008                 Levures, ModŹles et Outils (Yeasts, Models and Tools) Talk 8th Meeting, La Colle sur Loup, France

2005                 MENRT Doctoral grant from the “MinistŹre de l'Enseignement supérieur et de la Recherche (French Science and Education Ministry)

Completed Research Support

Fellow Award                            07/01/2011-06/31/2012                                                                         $47,210

Ellison Medical Foundation / American Federation for Aging Research (AFAR) Postdoctoral Fellowship in Aging Research

New ALS and FTLD disease genes: role of RNA-binding proteins

The major goals of this project are to sequence toxic, aggregation-prone candidate genes previously identified by yeast screen in Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal lobar degeneration (FTLD) patient samples and to define the functional significance of candidate ALS and FTLD disease genes and mutations.

Future Research Plan Summary

Misfolded protein accumulation is a frequent hallmark of neurological diseases but, for many of them, the mechanisms underlying this aggregation still remain unknown. From my past studies on prions and amyloids, and my current ones on ALS, I have always been interested in understanding by which processes proteins start to behave abnormally and what the triggers of such mechanisms are.

Simple model organisms, like yeast, have proven to be a fast and convenient starting point for studying early mechanisms leading to protein accumulation and toxicity, which can then be translated to a more complex model. Coupled with new sequencing techniques that allow us to get the complete exome of a small family in a matter of weeks, this is a very convenient way to discover new partners in crime in already well studied neurodegenerative diseases, but also, more interestingly, in the rare ones.

Access to large cohorts of patients, for large scale systematic studies, or to small families, for rare or orphan disease research, would be a fantastic opportunity to find new genes or new variants involved in a specific disease, that can be then complemented by functional studies in a simple model organism, or cell culture model to test these novel variants for pathogenicity.

References

Pr. Christophe Cullin: Professeur de Génétique ; Université Bordeaux Segalen ; Bordeaux FRANCE

                      

 

Dr. Aaron Gitler: Associate Professor of Genetics ; Stanford University ; Stanford, CA USA

                      

 

Dr. James Shorter: Associate Professor of Biochemistry and Biophysics ; University of Pennsylvania ; Philadelphia, PA USA