NOVEL ALS MODELS

Developing novel models of Amyotrophic Lateral Sclerosis using motor neuron cultures and zebrafish

Coordinatore	INSTITUT DU CERVEAU ET DE LA MOELLE EPINIERE FONDATION    more  Organization address address: BOULEVARD DE L'HOPITAL 47 city: PARIS postcode: 75013 contact info Titolo: Ms. Nome: Iwona Cognome: Jablonska Email: send email Telefono: +33 1 57 27 4745 Fax: +33 1 57 27 40 27
Nazionalità Coordinatore	France [FR]
Totale costo	100˙000 €
EC contributo	100˙000 €
Programma	FP7-PEOPLE Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013)
Code Call	FP7-PEOPLE-2011-CIG
Funding Scheme	MC-CIG
Anno di inizio	2011
Periodo (anno-mese-giorno)	2011-10-01   -   2015-09-30

 Partecipanti

#	participant	country	role	EC contrib. [€]
1	INSTITUT DU CERVEAU ET DE LA MOELLE EPINIERE FONDATION  Organization address address: BOULEVARD DE L'HOPITAL 47 city: PARIS postcode: 75013 contact info Titolo: Ms. Nome: Iwona Cognome: Jablonska Email: send email Telefono: +33 1 57 27 4745 Fax: +33 1 57 27 40 27	FR (PARIS)	coordinator	100˙000.00

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 Obiettivo del progetto (Objective)

'In 2008, I led a team that identified mutations in the TAR DNA binding protein (TARDBP) gene that encodes TDP-43 in ALS patients, which is enriched in inclusion bodies present in motor neurons from ALS patients. Also, mutations in the fused in sarcoma (FUS) gene were identified in ALS patients, with FUS involved in similar molecular mechanisms as TDP-43. This project aims to elucidate mechanisms involved in motor neuron degeneration caused by TDP-43 and FUS and to develop in vivo models to discover potential ALS therapies. Mutant TDP-43 causes degeneration in motor neurons from primary spinal cord cultures. Injection of mutant FUS in these cells will be conducted to determine if motor neurons are selective vulnerable to mutant TDP-43 or FUS. We also aim to characterize protein partners of mutant FUS/TDP-43 using immunoprecipitation and proteomic studies. Zebrafish is an excellent vertebrate model well suited for multigenic analysis and chemical screening in development and disease. Preliminary results suggest that knock-down of tardbp or fus as well as overexpression of mutant FUS and TDP-43 cause deficits in locomotory behavior and delayed axonal outgrowth in motor neurons from zebrafish. I am currently undertaking a multigenic analysis of TARDBP and FUS and previously ALS-related genes (SOD1, ALS2, VAPB) to discover whether common pathogenic pathways lead to motor neuron disorder. Finally, transgenic lines expressing mutant TDP-43 or FUS and fish lines with deletion of tardbp or fus genes are being generated and screened for motor neuron phenotypes. These lines will represent optimal ALS models to determine in vivo molecular mechanisms of pathogenesis. Further, our group is developing an automated platform in order to screen a large library of pharmaceutical compounds. This screen should propose compounds that are able to reverse the motor neuron specific phenotype in vivo and could be tested for therapeutically in ALS patients.'