{"doi":"10.1038/s42003-024-06071-2","title":"The nuclear import receptor Kapβ2 modifies neurotoxicity mediated by poly(GR) in C9orf72-linked ALS/FTD","abstract":"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","year":2024,"id":454311,"datarank":0.31191623125197543,"base_score":2.0794415416798357,"endowment":2.0794415416798357,"self_citation_contribution":0.31191623125197543,"citation_network_contribution":0.0,"self_endowment_contribution":0.31191623125197543,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":7,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9567,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1165815,"name":"V. Kankate","orcid":null,"position":1,"is_corresponding":false},{"id":889980,"name":"Sindhu Sriramoji","orcid":null,"position":2,"is_corresponding":false},{"id":348840,"name":"Karthik Krishnamurthy","orcid":"0000-0003-2552-8912","position":3,"is_corresponding":false},{"id":812659,"name":"Shashirekha S. Markandaiah","orcid":null,"position":4,"is_corresponding":false},{"id":812095,"name":"Brandie Morris Verdone","orcid":"0000-0001-7550-8536","position":5,"is_corresponding":false},{"id":897519,"name":"Amandeep Girdhar","orcid":"0000-0002-0523-6683","position":6,"is_corresponding":false},{"id":225249,"name":"Andrew T. Nelson","orcid":"0000-0002-2591-0428","position":7,"is_corresponding":false},{"id":1277527,"name":"Linda Blake Rivas","orcid":"0000-0002-8878-3729","position":8,"is_corresponding":false},{"id":1277889,"name":"Andrew Boehringer","orcid":null,"position":9,"is_corresponding":false},{"id":285353,"name":"Aaron R. Haeusler","orcid":"0000-0001-5566-3707","position":10,"is_corresponding":false},{"id":348843,"name":"Piera Pasinelli","orcid":"0000-0002-3385-2707","position":11,"is_corresponding":false},{"id":539723,"name":"Lin Guo","orcid":"0000-0002-2589-9513","position":12,"is_corresponding":false},{"id":348844,"name":"Davide Trotti","orcid":"0000-0001-6338-6404","position":13,"is_corresponding":false},{"id":812096,"name":"M.E. Cicardi","orcid":"0000-0001-9490-303X","position":0,"is_corresponding":true}],"reference_count":57,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:03:07.923686Z","pmid":"38548902","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}