{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Cicardi ME"],"funding":["U.S. Department of Health &amp; Human Services | NIH | National Institute of General Medical Sciences","U.S. Department of Health &amp; Human Services | NIH | National Institute of Neurological Disorders and Stroke","NIA NIH HHS","U.S. Department of Health &amp; Human Services | NIH | National Institute on Aging","NINDS NIH HHS","NIGMS NIH HHS"],"pagination":["376"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC10978903"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["7(1)"],"pubmed_abstract":["Expanded intronic G<sub>4</sub>C<sub>2</sub> repeats in the C9ORF72 gene cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). These intronic repeats are translated through a non-AUG-dependent mechanism into five different dipeptide repeat proteins (DPRs), including poly-glycine-arginine (GR), which is aggregation-prone and neurotoxic. Here, we report that Kapβ2 and GR interact, co-aggregating, in cultured neurons in-vitro and CNS tissue in-vivo. Importantly, this interaction significantly decreased the risk of death of cultured GR-expressing neurons. Downregulation of Kapβ2 is detrimental to their survival, whereas increased Kapβ2 levels mitigated GR-mediated neurotoxicity. As expected, GR-expressing neurons displayed TDP-43 nuclear loss. Raising Kapβ2 levels did not restore TDP-43 into the nucleus, nor did alter the dynamic properties of GR aggregates. Overall, our findings support the design of therapeutic strategies aimed at up-regulating Kapβ2 expression levels as a potential new avenue for contrasting neurodegeneration in C9orf72-ALS/FTD."],"journal":["Communications biology"],"pubmed_title":["The nuclear import receptor Kapβ2 modifies neurotoxicity mediated by poly(GR) in C9orf72-linked ALS/FTD."],"pmcid":["PMC10978903"],"funding_grant_id":["NS114128","AG057882","GM138109","R35 GM138109","R01 NS109150","R21 NS090912","RF1 AG057882","NS109150","NS090912","RF1 NS114128"],"pubmed_authors":["Krishnamurthy K","Verdone BM","Markandaiah SS","Haeusler AR","Pasinelli P","Girdhar A","Boehringer A","Cicardi ME","Sriramoji S","Guo L","Rivas LB","Trotti D","Kankate V","Nelson A"],"additional_accession":[]},"is_claimable":false,"name":"The nuclear import receptor Kapβ2 modifies neurotoxicity mediated by poly(GR) in C9orf72-linked ALS/FTD.","description":"Expanded intronic G<sub>4</sub>C<sub>2</sub> repeats in the C9ORF72 gene cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). These intronic repeats are translated through a non-AUG-dependent mechanism into five different dipeptide repeat proteins (DPRs), including poly-glycine-arginine (GR), which is aggregation-prone and neurotoxic. Here, we report that Kapβ2 and GR interact, co-aggregating, in cultured neurons in-vitro and CNS tissue in-vivo. Importantly, this interaction significantly decreased the risk of death of cultured GR-expressing neurons. Downregulation of Kapβ2 is detrimental to their survival, whereas increased Kapβ2 levels mitigated GR-mediated neurotoxicity. As expected, GR-expressing neurons displayed TDP-43 nuclear loss. Raising Kapβ2 levels did not restore TDP-43 into the nucleus, nor did alter the dynamic properties of GR aggregates. Overall, our findings support the design of therapeutic strategies aimed at up-regulating Kapβ2 expression levels as a potential new avenue for contrasting neurodegeneration in C9orf72-ALS/FTD.","dates":{"release":"2024-01-01T00:00:00Z","publication":"2024 Mar","modification":"2026-05-29T11:22:04.889Z","creation":"2025-04-05T23:19:03.873Z"},"accession":"S-EPMC10978903","cross_references":{"pubmed":["38548902"],"doi":["10.1038/s42003-024-06071-2"]}}