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Depletion of TDP‐43 affects Drosophila motoneurons terminal synapsis and locomotive behavior
Author(s) -
Feiguin Fabian,
Godena Vinay K.,
Romano Giulia,
D'Ambrogio Andrea,
Klima Raffaella,
Baralle Francisco E.
Publication year - 2009
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/j.febslet.2009.04.019
Subject(s) - amyotrophic lateral sclerosis , neurodegeneration , c9orf72 , tardbp , biology , sod1 , neuroscience , frontotemporal dementia , drosophila melanogaster , ubiquitin , microbiology and biotechnology , genetics , medicine , pathology , dementia , gene , disease
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.