Open Close
Pons, M., Miguel, L., Miel, C., Avequin, T., Juge, F., Frebourg, T., Campion, D., Lecourtois, M. (2017). Splicing factors act as genetic modulators of TDP-43 production in a new autoregulatory TDP-43 Drosophila model.  Hum. Mol. Genet. 26(17): 3396--3408.
FlyBase ID
Publication Type
Research paper

TDP-43 is a critical RNA-binding factor associated with RNA metabolism. In the physiological state, maintaining normal TDP-43 protein levels is critical for proper physiological functions of the cells. As such, TDP-43 expression is tightly regulated through an autoregulatory negative feedback loop. TDP-43 is a major disease-causing protein in Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Lobar Degeneration (FTLD). Several studies argue for a pathogenic role of elevated TDP-43 levels in these disorders. Modulating the cycle of TDP-43 production might therefore provide a new therapeutic strategy. In this study, we developed a new transgenic Drosophila model mimicking the TDP-43 autoregulatory feedback loop in order to identify genetic modulators of TDP-43 protein steady-state levels in vivo. First, we showed that our TDP-43_TDPBR Drosophila model recapitulates key features of the TDP-43 autoregulatory processes previously described in mammalian and cellular models, namely alternative splicing events, differential usage of polyadenylation sites, nuclear retention of the transcript and a decrease in steady-state mRNA levels. Using this new Drosophila model, we identified several splicing factors, including SF2, Rbp1 and Sf3b1, as genetic modulators of TDP-43 production. Interestingly, our data indicate that these three RNA-binding proteins regulate TDP-43 protein production, at least in part, by controlling mRNA steady-state levels.

PubMed ID
PubMed Central ID
Associated Information
Associated Files
Other Information
Secondary IDs
    Language of Publication
    Additional Languages of Abstract
    Parent Publication
    Publication Type
    Hum. Mol. Genet.
    Human Molecular Genetics
    Publication Year
    Data From Reference