Research on cell lines is often the tell-tell sign of low resources combined with great ambitions. Usually this does not give good results. A recent article on the excellent eLife magazine provide a brilliant counter example to the above thesis.
Magda Luciana Atilano and her colleagues from University College London and Max Planck Institute for Biology of Ageing show that modulating insulin signaling in mammalian cells lowers C9orf72 repeat expansion.
This might seems unlikely as insulin is involved in cell’s metabolism while C9orf72 regulate endosomal trafficking and autophagy in neuronal cells and primary neurons. Those two unrelated topics at first glance.
However C9orf72 regulates GTPase such as the Rag GTPases that simulate mTORC1 and so regulate macro-autophagy. Intuitively one can imagine that increased autophagy could remedy to C9orf72 repeats, yet how C9orf72 toxic proteins are isolated and eliminated by autophagy is not known.
The authors further demonstrate that activation of insulin/Igf signalling can mitigate multiple neurodegenerative phenotypes in flies expressing either expanded G4C2 repeats or the toxic dipeptide repeat protein poly-GR. They found that levels of poly-GR were reduced when components of the insulin/Igf signaling pathway was genetically activated in diseased flies, suggesting a mechanism of rescue. Modulating insulin signaling in mammalian cells also lowers poly-GR levels. Remarkably, systemic injection of insulin improves the survival of flies expressing G4C2 repeats.
Overall, the scientist’s work suggest that modulation of insulin/Igf signalling could be an effective therapeutic approach against C9orf72 ALS/FTD.
However caution must be exercised: Flies are not humans. In invertebrates, the intracellular insulin-like signaling (ILS) pathway is regulated by multiple peptides, known as insulin-like peptides. In mammals, the ILS pathway is mediated through the binding of IGF-1 to the human IGF-1 receptor (IGF-1R) in the plasma membrane. So it remains to see how those findings would translate in humans.
This book retraces the main achievements of ALS research over the last 30 years, presents the drugs under clinical trial, as well as ongoing research on future treatments likely to be able stop the disease in a few years and to provide a complete cure in a decade or two.