{
  "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 repeat associated non-canonical translation. The expanded repeat also suppresses transcription of the major transcript variant (Variant 2) which comprises 90% of the C9ORF72 levels in healthy cells, leading to an additional loss-of-function effect. Examining the sequence, structure, and ribosome occupancy of Variant 2’s mRNA leader in detail, we found that translation of C9ORF72 is tightly regulated through a multi-layered system. To deconvolute this system, we conducted a mutant screen and developed a method to evaluate the results quantitatively. We found that near-cognate start codons in all three frames, a start-stop element in frame 2, a uTranslon in frame 1, and secondary structures cooperate to keep baseline C9ORF72 translation low. Further, initiation at upstream near-cognate start codons reduces the impact of both the start-stop and the uTranslon, effectively buffering their repressive function and creating a feedforward loop. A strong secondary structure in the Variant 2-specific sequence further modulates initiation at all the elements. We hypothesize that this buffered repressor system has evolved to ensure reliable, noise-insensitive expression of this critical regulator of neuronal function. Finally, we used ADAR-based RNA editing of specific sites in Variant 2’s mRNA leader, increasing translation of the gene and providing a novel avenue to rescue the loss-of-function phenotype in disease.",
  "abstract_shown": true,
  "affiliations": [],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 18,
  "authors": [
    {
      "name": "Solomon A. Haizel"
    },
    {
      "name": "Alfredo Vidal Ceballos"
    },
    {
      "name": "Alice Nayoung Ko"
    },
    {
      "name": "Lucas Lyu"
    },
    {
      "name": "Lauren Manning"
    },
    {
      "name": "Xinyi Ge"
    },
    {
      "name": "Violet Park"
    },
    {
      "name": "Huijing Zou"
    },
    {
      "name": "Churong Cheng"
    },
    {
      "name": "Richmond Afful"
    },
    {
      "name": "Serena Kher"
    },
    {
      "name": "Anthony Widjaja"
    },
    {
      "name": "Joanetta Jean-Baptiste"
    },
    {
      "name": "Sasha Khazhinsky"
    },
    {
      "name": "Pieter Spealman"
    },
    {
      "name": "Alisha N. Jones"
    },
    {
      "name": "Leos Shivaya Valasek"
    },
    {
      "name": "Christine Vogel",
      "orcid": "0000-0002-2856-3118"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/8gdnmthh25w3f.bib",
  "cited_by": 0,
  "doi": "10.1101/2025.08.09.669471",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13738376/",
  "id": "8gdnmthh25w3f",
  "issns": [
    "2692-8205"
  ],
  "landing_url": "https://doi.org/10.1101/2025.08.09.669471",
  "language": "en",
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Article"
    ],
    [
      "openalex",
      "1312|RNA and protein synthesis mechanisms"
    ]
  ],
  "openalex": "W4413172401",
  "pdf_url": "https://www.biorxiv.org/content/biorxiv/early/2025/08/09/2025.08.09.669471.full.pdf",
  "pmcid": "PMC13738376",
  "pmid": "42995797",
  "published": "2026-10-22",
  "publisher": "Cold Spring Harbor Laboratory Preprints",
  "ris": "https://research.draconitic.com/paper/8gdnmthh25w3f.ris",
  "sources": [
    {
      "first_seen": "2026-11-09T12:23:22Z",
      "native_id": "PMC13738376",
      "source": "pmc",
      "url": "https://doi.org/10.1101/2025.08.09.669471"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|RNA and protein synthesis mechanisms",
      "subfield": "molecular-biology"
    }
  ],
  "title": "Multi-level repression ensures tight translation control of C9ORF72",
  "title_text": "Multi-level repression ensures tight translation control of C9ORF72",
  "type": "preprint",
  "updated_at": "2026-11-09T12:23:22Z",
  "url": "https://research.draconitic.com/paper/8gdnmthh25w3f",
  "venue": "bioRxiv",
  "versions": []
}