{"corpus_id":257914625,"paper_sha":"9306eb6c0d0d9ffb7db423903f857ae3dec8e722","doi":"10.1038/s41467-023-43872-1","arxiv_id":null,"pmid":38092738,"pmcid":"10719400","mag_id":null,"dblp_id":null,"acl_id":null,"title":"The ALS/FTD-related C9orf72 hexanucleotide repeat expansion forms RNA condensates through multimolecular G-quadruplexes","year":2023,"publication_date":"2023-09-04","venue":"bioRxiv","journal":{"name":"Nature Communications","pages":null,"volume":"14"},"journal_issn":null,"journal_title":null,"publication_types":["JournalArticle"],"pubmed_pub_types":["Journal Article","Research Support, Non-U.S. Gov't"],"s2_fields_of_study":["Biology","Medicine"],"reference_count":87,"citation_count":42,"influential_citation_count":1,"is_open_access":true,"arxiv_categories":null,"arxiv_license":null,"arxiv_journal_ref":null,"mesh_headings":[{"d":"Humans","mj":false,"ui":"D006801"},{"d":"Frontotemporal Dementia","mj":true,"qs":[{"q":"genetics","mj":false,"ui":"Q000235"}],"ui":"D057180"},{"d":"Amyotrophic Lateral Sclerosis","mj":true,"qs":[{"q":"genetics","mj":false,"ui":"Q000235"}],"ui":"D000690"},{"d":"RNA","mj":false,"qs":[{"q":"genetics","mj":false,"ui":"Q000235"},{"q":"chemistry","mj":false,"ui":"Q000737"}],"ui":"D012313"},{"d":"G-Quadruplexes","mj":true,"ui":"D054856"},{"d":"C9orf72 Protein","mj":false,"qs":[{"q":"genetics","mj":false,"ui":"Q000235"}],"ui":"D000073885"},{"d":"DNA Repeat Expansion","mj":false,"qs":[{"q":"genetics","mj":false,"ui":"Q000235"}],"ui":"D042622"}],"chemicals":[{"n":"RNA","ui":"D012313","reg":"63231-63-0"},{"n":"C9orf72 Protein","ui":"D000073885","reg":"0"},{"n":"C9orf72 protein, human","ui":"C568651","reg":"0"}],"comments_corrections":null,"source_flags":5,"s2_open_access_pdf_url":"https://www.nature.com/articles/s41467-023-43872-1.pdf","s2_open_access_landing_url":"https://www.semanticscholar.org/paper/9306eb6c0d0d9ffb7db423903f857ae3dec8e722","s2_open_access_license":"CCBY","s2_open_access_status":"GOLD","pmc_open_access_pdf_url":null,"pmc_open_access_landing_url":null,"pmc_open_access_license":null,"pmc_open_access_status":null,"unpaywall_open_access_pdf_url":null,"unpaywall_open_access_landing_url":null,"unpaywall_open_access_license":null,"unpaywall_open_access_status":null,"abstract":"Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative diseases that exist on a clinico-pathogenetic spectrum, designated ALS/FTD. The most common genetic cause of ALS/FTD is the expansion of the intronic hexanucleotide repeat (GGGGCC)nin C9orf72. Here, we investigated the formation of nucleic-acid secondary structures in these expansion repeats, and their role in generating condensates characteristic of the diseases. We observed significant aggregation of the hexanucleotide sequence (GGGGCC)n, which we associated to the formation of multimolecular G-quadruplexes (mG4s), using a range of biophysical techniques. Exposing the condensates to G4-unfolding conditions led to prompt disassembly, highlighting the key role of mG4-formation in the condensation process. We further validated the biological relevance of our findings by demonstrating the ability of a G4-selective fluorescent probe to penetrate C9orf72 mutant human motor neurons derived from ALS patients, which revealed clear fluorescent signal in putative condensates. Our findings strongly suggest that RNA G- rich repetitive sequences can form protein-free condensates sustained by multimolecular G- quadruplexes, highlighting their potential relevance as therapeutic targets for C9orf72 mutation related ALS and FTD.","claims":[{"public_id":"cl_ef66129d6c9d6b2661d68057931da4ba","status":"active","text":"A G4-selective fluorescent probe enters C9orf72 mutant human motor neurons and produces a fluorescent signal in putative condensates.","confidence":0.93,"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/claims/cl_ef66129d6c9d6b2661d68057931da4ba"},{"public_id":"cl_43d819a84a2d576ccea12602fc9b942d","status":"active","text":"G4-unfolding conditions rapidly disassemble the condensates, indicating that multimolecular G-quadruplex formation is essential for the condensation process.","confidence":0.96,"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/claims/cl_43d819a84a2d576ccea12602fc9b942d"},{"public_id":"cl_ced480f4bf48b6bf38bf2682084f955c","status":"active","text":"Multimolecular G-quadruplexes in C9orf72 mutation-related ALS and FTD are potential therapeutic targets.","confidence":0.86,"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/claims/cl_ced480f4bf48b6bf38bf2682084f955c"},{"public_id":"cl_87b47cca8ee8a0cab0905ee5a0a15c4a","status":"active","text":"RNA G-rich repetitive sequences can form protein-free condensates sustained by multimolecular G-quadruplexes.","confidence":0.92,"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/claims/cl_87b47cca8ee8a0cab0905ee5a0a15c4a"},{"public_id":"cl_a1daf9ca9f2e8dfd5fd7d0d9be370b7a","status":"active","text":"The C9orf72 hexanucleotide repeat sequence (GGGGCC)n forms RNA condensates through multimolecular G-quadruplexes.","confidence":0.98,"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/claims/cl_a1daf9ca9f2e8dfd5fd7d0d9be370b7a"}],"concepts":[{"public_id":"co_19ff6fe61691b065bc35ad2416e78b0b","status":"active","name":"C9orf72 hexanucleotide repeat expansion","description":"An intronic GGGGCC repeat expansion in the C9orf72 gene associated with ALS/FTD.","types":["genetic alteration"],"aliases":["(GGGGCC)n","hexanucleotide repeat (GGGGCC)n"],"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/concepts/co_19ff6fe61691b065bc35ad2416e78b0b"},{"public_id":"co_2a425e1e62ff9a74c698cc8fd078118a","status":"active","name":"multimolecular G-quadruplexes","description":"Higher-order G-quadruplex structures formed by multiple nucleic-acid strands or repeats.","types":["nucleic-acid structure"],"aliases":["mG4s","G-quadruplexes","mG4"],"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/concepts/co_2a425e1e62ff9a74c698cc8fd078118a"},{"public_id":"co_5d262475d2a0f348924ff6633d396e63","status":"active","name":"RNA G-rich repetitive sequences","description":"RNA sequences enriched in guanine and arranged as tandem repeats.","types":["nucleic-acid sequence"],"aliases":["G-rich repetitive 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