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

Abstract

SummaryExpanded intronic G4C2 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 Kap{beta}2 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 {beta}2 is detrimental to the survival of neurons only if GR is expressed, whereas increased Kap {beta}2 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 Kap{beta}2 was over-expressed. These findings support the design of therapeutic strategies aimed at modulating Kap {beta}2 levels as a potential new avenue for contrasting neurodegeneration in C9orf72-ALS/FTD.