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Reference Report
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| Citation | Miguel, L., Frébourg, T., Campion, D., Lecourtois, M. (2011). Both cytoplasmic and nuclear accumulations of the protein are neurotoxic in Drosophila models of TDP-43 proteinopathies. Neurobiol. Disease 41(2): 398--406. (Export to RIS) | ||
| FlyBase ID | FBrf0212655 | ||
| Publication Type | Research paper | ||
| PubMed ID | 20951205 | ||
| PubMed Abstract | 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. | ||
| DOI | 10.1016/j.nbd.2010.10.007 | ||
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| Language of Publication | English | ||
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| Publication Type | Journal | ||
| Abbreviation | Neurobiol. Disease | ||
| Title | Neurobiology of Disease | ||
| Publication Year | 1994- | ||
| ISBN/ISSN | 0969-9961 | ||
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Data from Reference
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| Alleles (8)
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| Constructs (5)
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| Genes (3)
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| Insertions (3)
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| Natural transposons (1)
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