Rapamycin alleviates pathogenesis of a new Drosophila model of ALS-TDP

Abstract

TDP-43 is a multi-functional RNA/DNA-binding protein, well-conserved among many species including mammals and Drosophila. However, it is also a major component of the pathological inclusions associated with degenerating motor neurons of amyotrophic lateral sclerosis (ALS). Further, TDP-43 is a signature protein in one subtype of frontotemporal degeneration, FTLD-U. Currently, there are no effective drugs for these neurodegenerative diseases. We describe the generation and characterization of a new fly model of ALS-TDP with transgenic expression of the Drosophila ortholog of TDP-43, dTDP, in adult flies under the control of a temperature-sensitive motor neuron-specific GAL4, thus bypassing the deleterious effect of dTDP during development. Diminished lifespan as well as impaired locomotor activities of the flies following induction of dTDP overexpression have been observed. Dissection of the T1/T2 region of the thoracic ganglia has revealed loss of these neurons. To counter the defects in this fly model of ALS-TDP, we have examined the therapeutic effects of the autophagy activator, rapamycin. Although harmful to the control flies, administration of 400 μM rapamycin before the induction of dTDP overexpression can significantly reduce the number of neurons bearing dTDP (+) aggregates, as well as partially rescue the diminished lifespan and locomotive defects of the ALS-TDP flies. Furthermore, we identify S6K, a downstream mediator of the TOR pathway, as one genetic modifier of dTDP. In sum, this Drosophila model of ALS-TDP under temporal and spatial control presents a useful new genetic tool for the screening and validation of therapeutic drugs for ALS. Furthermore, the data support our previous finding that autophagy activators including rapamycin are potential therapeutic drugs for the progression of neurodegenerative diseases with TDP-43 proteinopathies.

Keywords:

• Amyotrophic lateral sclerosis
• D42^ts-GAL4
• Drosophila
• lifespan
• locomotor activity
• TDP-43

Acknowledgements

We thank Dr. Cheng-Ting Chien of IMB for the assistance with use of the countercurrent apparatus, and Ms. Sue-Ping Lee of IMB for her help on the confocal microscopy analysis. We also thank Dr. Gabor Juhasz at the Eotvos Lorand University and Dr. Tor Erik Rusten at the University of Oslo for providing the anti-Drosophila p62 antibodies, and Dr. James B. Skeath at Washington University, St. Louis, for the anti-Drosophila HB9 antibody. This research was supported by the National Science Council (NSC) and the Academia Sinica, Taipei, Taiwan. C.-K. J. Shen is a Senior Investigator Awardee of Academia Sinica.

Declaration of interest

The authors report no declarations of interest.

Supplementary materials available online

Supplementary Figure 1 and Table to be found online at http://informahealthcare.com/doi/abs/10.3109/01677063.2015.1077832.