Depletion of TDP-43 affects Drosophila motoneurons terminal synapsis and locomotive behavior.
Pathological modifications in the highly conserved and ubiquitously expressed heterogeneous ribonucleoprotein TDP-43 were recently associated to neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), a late-onset disorder that affects predominantly motoneurons [Neumann, M. et al. (2006) Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314, 130-133, Sreedharan, J. et al. (2008) TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science 319, 1668-1672, Kabashi, E. et al. (2008) TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis. Nat. Genet. 40, 572-574]. However, the function of TDP-43 in vivo is unknown and a possible direct role in neurodegeneration remains speculative. Here, we report that flies lacking Drosophila TDP-43 appeared externally normal but presented deficient locomotive behaviors, reduced life span and anatomical defects at the neuromuscular junctions. These phenotypes were rescued by expression of the human protein in a restricted group of neurons including motoneurons. Our results demonstrate the role of this protein in vivo and suggest an alternative explanation to ALS pathogenesis that may be more due to the lack of TDP 43 function than to the toxicity of the aggregates.
Feiguin
Fabian
F
International Centre for Genetic Engineering and Biotechnology, Padriciano 99, Trieste, Italy. feiguin@icgeb.org
Godena
Vinay K
VK
Romano
Giulia
G
D'Ambrogio
Andrea
A
Klima
Raffaella
R
Baralle
Francisco E
FE
D000483:Alleles; D000818:Animals; D030801:Animals, Genetically Modified; D001522:Behavior, Animal; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D004330:Drosophila / Q000378:metabolism*; D006801:Humans; D009043:Motor Activity / Q000235:genetics*; D009046:Motor Neurons / Q000378:metabolism*; D010641:Phenotype; D017729:Presynaptic Terminals / Q000378:metabolism*
D004268:DNA-Binding Proteins