KapBeta2 is a modifier of the C9orf72-linked glycine-arginine dipeptide neurotoxicity

cicardi, M. e.; Kankate, V.; Sriramoji, S.; Krishnamurthy, K.; ShamamandriMarkandaiah, S.; Verdone-Morris, B.; Girdhar, A.; Nelson, A. T.; Rivas, L. B.; Boehringer, A.; Haeusler, A.; Pasinelli, P.; Guo, L.; Trotti, D.

doi:10.1101/2022.09.30.510384

bioRxiv · 10.1101/2022.09.30.510384

KapBeta2 is a modifier of the C9orf72-linked glycine-arginine dipeptide neurotoxicity

cicardi, M. e.·Kankate, V.·Sriramoji, S.·Krishnamurthy, K.·ShamamandriMarkandaiah, S.·Verdone-Morris, B.·Girdhar, A.·Nelson, A. T.·Rivas, L. B.·Boehringer, A.·Haeusler, A.·Pasinelli, P.·Guo, L.·Trotti, D.

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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.

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cicardi, M. e., Kankate, V., Sriramoji, S., Krishnamurthy, K., ShamamandriMarkandaiah, S., Verdone-Morris, B., Girdhar, A., Nelson, A. T., Rivas, L. B., Boehringer, A., Haeusler, A., Pasinelli, P., Guo, L., Trotti, D.. 2022-10-03. KapBeta2 is a modifier of the C9orf72-linked glycine-arginine dipeptide neurotoxicity. https://doi.org/10.1101/2022.09.30.510384

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