{
  "abstract": "The hexanucleotide repeat expansion in C9orf72 gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD). The C9orf72 protein forms a complex with SMCR8 and WDR41 (CSW), which functions as a GTPase-activating protein (GAP) regulating ARF1 and RAB small GTPases. While these findings implicated ARF1-GAP dysregulation in ALS/FTD and supported ARF1 suppression as potential intervention, small molecules that modulate ARF1-CSW interactions are lacking. In this study, we demonstrated upregulation of tyrosine-phosphorylated (Tyr-782) ASAP1 (also known as AMAP1, DDEF1, or Centaurin β4), an ARF-GAP, in human motor cortex of both sporadic ALS and ALS with C9orf72 mutations. Ectopic C9orf72 expression partially mimicked the effects of a known ARF1 inhibitor brefeldin A to disperse Golgi apparatus. Computer-aided rational drug design with high-throughput in-silico screening identified MCULE-5,095,997,944 (Named as SCC944) as a ARF1-CSW modulator. SCC944 binds directly to ARF1 and reduced GTP-bound ARF1 levels upon ARF1 activation. SCC944 demonstrated brefeldin A-like ARF1-dependent alteration of organelle organization including Golgi, microtubules, and mitochondria, but also a protein trafficking pattern that is distinct from brefeldin A mechanism. These studies identified the first small molecule targeting ARF1-CSW interaction and further support ARF1 modulation as a potential therapeutic approach for ALS/FTD.",
  "abstract_shown": true,
  "affiliations": [],
  "article_type": null,
  "arxiv": null,
  "author_total": 7,
  "authors": [
    {
      "name": "Emma Dixon"
    },
    {
      "name": "Fereshteh Azimian"
    },
    {
      "name": "Angelina Joby Chacko"
    },
    {
      "name": "Rodney Tatum"
    },
    {
      "name": "Christi Boykin"
    },
    {
      "name": "Yan-Hua Chen"
    },
    {
      "name": "Qun Lu",
      "orcid": "0000-0003-3545-7142"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/16xp85my9g708.bib",
  "cited_by": 0,
  "doi": "10.1038/s41598-026-72708-3",
  "fulltext_url": null,
  "id": "16xp85my9g708",
  "issns": [
    "2045-2322"
  ],
  "landing_url": "https://www.nature.com/articles/s41598-026-72708-3",
  "language": null,
  "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": [
    [
      "openalex",
      "2728|Amyotrophic Lateral Sclerosis Research"
    ]
  ],
  "openalex": "W7218985812",
  "pdf_url": "https://www.nature.com/articles/s41598-026-72708-3_reference.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-03",
  "publisher": "Springer Science and Business Media LLC",
  "ris": "https://research.draconitic.com/paper/16xp85my9g708.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:19Z",
      "native_id": "10.1038/s41598-026-72708-3",
      "source": "crossref",
      "url": "https://www.nature.com/articles/s41598-026-72708-3"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2728|Amyotrophic Lateral Sclerosis Research",
      "subfield": "neurology"
    }
  ],
  "title": "Small molecules targeting ARF1 interaction with C9orf72:SMCR8:WDR41 complexes suppress its overactivation implicated in ALS/FTD",
  "title_text": "Small molecules targeting ARF1 interaction with C9orf72:SMCR8:WDR41 complexes suppress its overactivation implicated in ALS/FTD",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:17:19Z",
  "url": "https://research.draconitic.com/paper/16xp85my9g708",
  "venue": "Scientific Reports",
  "versions": []
}