Julien 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.
Lyce 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*, DAngelo 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*, Rbora
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, Modles et Outils (Yeasts, Models and Tools)
Talk 8th Meeting, La Colle sur Loup, France
2005 MENRT
Doctoral grant from the Ministre de l'Enseignement suprieur 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 Gntique ;
Universit 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
