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ZFIN ID: ZDB-PUB-110811-33
FUS and TARDBP but Not SOD1 Interact in Genetic Models of Amyotrophic Lateral Sclerosis
Kabashi, E., Bercier, V., Lissouba, A., Liao, M., Brustein, E., Rouleau, G.A, and Drapeau, P.
Date: 2011
Source: PLoS Genetics 7(8): e1002214 (Journal)
Registered Authors: Brustein, Edna, Drapeau, Pierre
Keywords: Zebrafish, Phenotypes, Motor neurons, Hyperexpression techniques, Embryos, Amyotrophic lateral sclerosis, Messenger RNA, Motor proteins
MeSH Terms:
  • Amyotrophic Lateral Sclerosis/genetics*
  • Amyotrophic Lateral Sclerosis/metabolism
  • Animals
  • DNA-Binding Proteins/genetics*
  • DNA-Binding Proteins/metabolism
  • Epistasis, Genetic
  • Humans
  • Models, Genetic*
  • Motor Activity/genetics
  • Mutation/genetics
  • Phenotype
  • RNA-Binding Protein FUS/genetics*
  • RNA-Binding Protein FUS/metabolism
  • Superoxide Dismutase/genetics*
  • Superoxide Dismutase/metabolism
  • Zebrafish/genetics
  • Zebrafish/metabolism
PubMed: 21829392 Full text @ PLoS Genet.
FIGURES
ABSTRACT
Mutations in the SOD1 and TARDBP genes have been commonly identified in Amyotrophic Lateral Sclerosis (ALS). Recently, mutations in the Fused in sarcoma gene (FUS) were identified in familial (FALS) ALS cases and sporadic (SALS) patients. Similarly to TDP-43 (coded by TARDBP gene), FUS is an RNA binding protein. Using the zebrafish (Danio rerio), we examined the consequences of expressing human wild-type (WT) FUS and three ALS–related mutations, as well as their interactions with TARDBP and SOD1. Knockdown of zebrafish Fus yielded a motor phenotype that could be rescued upon co-expression of wild-type human FUS. In contrast, the two most frequent ALS–related FUS mutations, R521H and R521C, unlike S57”Δ, failed to rescue the knockdown phenotype, indicating loss of function. The R521H mutation caused a toxic gain of function when expressed alone, similar to the phenotype observed upon knockdown of zebrafish Fus. This phenotype was not aggravated by co-expression of both mutant human TARDBP (G348C) and FUS (R521H) or by knockdown of both zebrafish Tardbp and Fus, consistent with a common pathogenic mechanism. We also observed that WT FUS rescued the Tardbp knockdown phenotype, but not vice versa, suggesting that TARDBP acts upstream of FUS in this pathway. In addition we observed that WT SOD1 failed to rescue the phenotype observed upon overexpression of mutant TARDBP or FUS or upon knockdown of Tardbp or Fus; similarly, WT TARDBP or FUS also failed to rescue the phenotype induced by mutant SOD1 (G93A). Finally, overexpression of mutant SOD1 exacerbated the motor phenotype caused by overexpression of mutant FUS. Together our results indicate that TARDBP and FUS act in a pathogenic pathway that is independent of SOD1.
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