{"doi":"10.1101/2025.08.09.669471","title":"Tight translation regulation of the canonical C9ORF72 through a multi-component system","abstract":"Abstract C9ORF72 is involved in multiple neuronal functions and a major factor in Amyotrophic Lateral Sclerosis, a fatal neurodegenerative disease. Pathogenicity is implemented through an intronic repeat expansion in the gene’s mRNA leader that produces long, repetitive RNA and dipeptides when translated through a non-canonical mechanism. In contrast, despite the presence of ribosome-occupied, regulatory elements in the mRNA leader, nothing is known about C9ORF72 translation regulation under normal conditions. Surprisingly, when analyzing a series of mutants of the C9ORF72 mRNA leader, we found that translation of C9ORF72 is tightly regulated through a multi-layer system. First, non-canonical, multi-initiation upstream open reading frames (nc-uORFs) in all three frames, a start-stop element in frame 2, and a canonical uORF in frame 1work together to keep baseline C9ORF72 translation very low. Second, a strong secondary structure enhances these repressive elements, mainly the two nc-uORFs in frames 0 and 2. Finally, as initiation at the nc-uORFs reduces initiation at the downstream start-stop, the nc-uORFs effectively dampen the start-stop’s repressive function, forming a feedforward loop. We hypothesize that this buffered repressor system has likely evolved to ensure reliable, noise-insensitive expression of this critical regulator of neuronal function.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":572418,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.952,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1479044,"name":"Adans Ko","orcid":null,"position":1,"is_corresponding":false},{"id":1479045,"name":"Lauren Manning","orcid":null,"position":2,"is_corresponding":false},{"id":1444327,"name":"Xinyi Ge","orcid":null,"position":3,"is_corresponding":false},{"id":1478580,"name":"Huijing Zou","orcid":"0000-0002-5656-5364","position":4,"is_corresponding":false},{"id":1479046,"name":"Churong Cheng","orcid":null,"position":5,"is_corresponding":false},{"id":1479047,"name":"Anthony Widjaja","orcid":null,"position":6,"is_corresponding":false},{"id":1479048,"name":"Joanetta Jean-Baptiste","orcid":null,"position":7,"is_corresponding":false},{"id":1479049,"name":"Sasha Khazhinsky","orcid":null,"position":8,"is_corresponding":false},{"id":332259,"name":"Pieter Spealman","orcid":"0000-0002-7105-284X","position":9,"is_corresponding":false},{"id":17888,"name":"Christine Vogel","orcid":"0000-0002-2856-3118","position":10,"is_corresponding":false},{"id":827505,"name":"Solomon Haizel","orcid":null,"position":0,"is_corresponding":true}],"reference_count":16,"raw_metadata":null,"created_at":"2026-07-19T02:57:23.653298Z","pmid":null,"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":[]}