Evolutionarily-conserved hnRNP A/B proteins functionally interact with human and Drosophila TAR DNA-binding protein 43 (TDP-43) [Gene Regulation]

February 3rd, 2014 by Romano, M., Buratti, E., Romano, G., Klima, R., Del Bel Belluz, L., Stuani, C., Baralle, F., Feiguin, F.

Human TDP-43 represents the main component of neuronal inclusions found in patients with neurodegenerative diseases, especially FTLD and ALS. In vitro and in vivo studies have shown that the TDP-43 Drosophila ortholog (TBPH) can biochemically and functionally overlap the properties of the human factor. The recent direct implication of the human hnRNPs A2B1 and A1, known TDP-43 partners, in the pathogenesis of multisystem proteinopathy and ALS, supports the hypothesis that the physical and functional interplay between TDP-43 and hnRNP A/B orthologs might play a crucial role in the pathogenesis of neurodegenerative diseases. To test this hypothesis and further validate the fly system as a useful model to study this type of diseases, we have now characterized human TDP-43 and drosophila TBPH similarity in terms of protein-protein interaction pathways. In this work, we show that TDP-43 and TBPH share the ability to associate in vitro with Hrp38/Hrb98DE/CG9983, the fruit fly ortholog of the human hnRNP A1/A2 factors. Interestingly, the protein regions of TDP-43 and Hrp38 responsible for reciprocal interactions are conserved through evolution. Functionally, experiments in HeLa cells demonstrate that TDP-43 is necessary for the inhibitory activity of Hrp38 on splicing. Finally, Drosophila in vivo studies show that Hrp38 deficiency produces locomotive defects and life span shortening in TDP-43 +/- animals. These results suggest that hnRNP protein levels can play a modulatory role on TDP-43 functions.
  • Posted in Journal of Biological Chemistry, Publications
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