A team lead by scientists at Thomas Jefferson University have demonstrated a new opportunity for intervening in ALS/FTD.
They worked on the hypothesis that aberrant arginine-rich dipeptide repeat (R-DPR) proteins are a key toxicity, aggregating with RNA binding proteins. They demonstrated that it was possible to disrupt the aggregation, though initially at the cost of the function of beneficial liquid-liquid phase separations that occur in stress granules and nucleoli, for example. Modification of the active protein Kapβ2 to be deficient for the nuclear localisation signal (NLS) enabled them, in vitro, to inhibit R-DPR toxicity without side-effect.
In one demonstration of this, neurones were exposed to combinations of an R-DPR with and without NLS-deficient Kapβ2 in the presence of DRAQ7 as a real-time reporter of toxicity resulting in cell death under the different treatments.
DRAQ7 again displayed its own ultra-low toxicity over long time-courses (here 18h), enabling such ground-breaking work.
Reference:
Kim, K.M., Girdhar, A., Cicardi, M.E. et al. NLS-binding deficient Kapβ2 reduces neurotoxicity via selective interaction with C9orf72-ALS/FTD dipeptide repeats. Commun Biol 8, 2 (2025). DOI:10.1038/s42003-024-07412-x
