The nuclear import receptor Kapβ2 modifies neurotoxicity mediated by poly(GR) in C9orf72-linked ALS/FTD

Summary: Expanded intronic G 4 C 2 repeats in the C9orf72 gene cause several cases of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). These repeats are translated through a non-AUG-dependent mechanism into five different dipeptides (DPRs), including poly-glycine-arginine (GR), which is aggregation-prone and eventually neurotoxic. Here, we report that Kapβ2 and GR interact, co-aggregating in primary neurons in-vitro and CNS tissue in-vivo . Importantly, this interaction improves the overall survival of neurons expressing GR. Downregulation of Kap β2 is detrimental to the survival of neurons only if GR is expressed, whereas increased Kap β2 levels mitigate GR-mediated neurotoxicity. notably, we did not find any changes in TDP-43 localization nor in the dynamic properties of the GR aggregates when Kapβ2 was over-expressed. These findings support the design of therapeutic strategies aimed at modulating Kap β2 levels as a potential new avenue for contrasting neurodegeneration in C9orf72-ALS/FTD.