Both cytoplasmic and nuclear accumulations of the protein are neurotoxic in Drosophila models of TDP-43 proteinopathies.
Recently, the TAR DNA-binding protein-43 (TDP-43) has been identified as a major constituent of nuclear and/or cytoplasmic ubiquitin-positive inclusions in patient with amyotrophic lateral sclerosis or frontotemporal lobar degeneration. Pathological proteins are abnormally hyperphosphorylated and partially cleaved to generate C-terminal fragments. In this issue, we addressed the mechanism underlying TDP-43 toxicity in vivo, using Drosophila as an experimental model. We developed new Drosophila transgenic models expressing different variants of full-length human TDP-43 proteins presenting different subcellular localizations: a wild-type form of hTDP-43 and two mutants forms of the protein, hTDP-43mutNLS and hTDP43mutNES, which lack nuclear localization signals (NLS) and nuclear export signals (NES), respectively. Using an inducible GAL4 system, we found that both nuclear and cytoplasmic accumulations of TDP-43 in adult neurons lead to reduction of lifespan in Drosophila, the gradient of toxicity being hTDP-43>hTDP-43mutNLS>hTDP43mutNES. This toxicity occurs regardless of inclusions formation. In the other hand, in retina, muscle and glial cells, only the accumulation of cytoplasmic species of TDP-43 was toxic. Biochemical data showed that human TDP-43 proteins expressed in adult fly neurons are abnormally phosphorylated on the disease-specific Ser409/Ser410 site and processed. In conclusion, our data show that TDP-43 expression in flies recapitulates several biochemical key features of human TDP-43 proteinopathies, including abnormal phosphorylation on a disease-specific site and processing of the protein. Moreover, our TDP-43 Drosophila models indicate that distinct pathways of TDP-43 toxicity might operate depending on the cell type.
InsermU614, IFRMP23, Rouen Institute for Medical Research and Innovation, Faculty of Medicine, University of Rouen, 22 Boulevard Gambetta, 76183 Rouen Cedex 01, France.
Laetitia
L
Miguel
Thierry
T
Frébourg
Dominique
D
Campion
Magalie
M
Lecourtois
D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D030801:Animals, Genetically Modified; D016923:Cell Death / Q000235:genetics; D002467:Cell Nucleus / Q000378:metabolism* / Q000473:pathology; D003593:Cytoplasm / Q000378:metabolism* / Q000473:pathology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D004195:Disease Models, Animal; D004331:Drosophila melanogaster / Q000166:cytology / Q000235:genetics / Q000378:metabolism; D057180:Frontotemporal Dementia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D057177:TDP-43 Proteinopathies / Q000235:genetics / Q000378:metabolism*
D004268:DNA-Binding Proteins