{
  "abstract": "Background. Nuclear TDP-43 depletion is a central pathological feature of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), but donor-to-donor variation can obscure transcriptomic associations in small postmortem cohorts. We reanalyzed public RNA-seq data from FACS-isolated NeuN-positive frontal-cortex neuronal nuclei to quantify gene-expression changes associated with nuclear TDP-43 loss while explicitly accounting for donor structure. Methods. The supplied GSE126542-derived matrix contained 62,754 genes across 12 libraries from seven donors, including five complete matched pairs. Source labels TDP-43 positive and TDP-43 negative were harmonized as nuclear TDP-43 retained and lost, respectively. After validation against featureCounts-assigned read counts, 44,225 genes with at least 10 total counts were analyzed using PyDESeq2. The primary model was ~ donor + nuclear_status; status-only and diagnosis-adjusted models were sensitivity analyses. The contrast was TDP-43 loss minus retained. Results. The donor-aware model identified 3,442 genes at false discovery rate (FDR) < 0.05: 1,865 lower and 1,577 higher in TDP-43-loss nuclei. STMN2 was consistently depleted (log2 fold change = -1.813, 95% Wald interval -2.229 to -1.396; FDR = 6.22e-15), corresponding to approximately 71.5% lower expression. Normalized STMN2 counts were lower in TDP-43-loss nuclei in all five complete donor pairs. TARDBP expression was also lower (log2 fold change = -0.606; FDR = 4.98e-6). In contrast, UNC13A whole-gene expression was modestly higher in the donor-aware model (log2 fold change = 0.372; FDR = 0.00622) and was not significant in either sensitivity model. Conclusions. Donor-aware analysis supports a robust association between nuclear TDP-43 loss and STMN2 depletion in this neuronal-nuclei cohort, alongside extensive but model-dependent transcriptomic variation. Whole-gene UNC13A expression cannot be used to infer UNC13A cryptic-exon inclusion or functional UNC13A depletion. No splice-junction, percent-spliced-in, isoform, or protein measurements were available; mechanistic claims therefore require junction-level and experimental validation.",
  "abstract_shown": true,
  "affiliations": [
    "Tongji Medical College of Huazhong University of Science and Technology,"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 2,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "A. CHAUDHARY"
    },
    {
      "name": "S. Yao"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/bjrg9x9jy9mms.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.10.27.762172",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.10.27.762172v1.full",
  "id": "bjrg9x9jy9mms",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.10.27.762172v1",
  "language": null,
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "neuroscience"
    ]
  ],
  "openalex": null,
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.10.27.762172v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-27",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/bjrg9x9jy9mms.ris",
  "sources": [
    {
      "first_seen": "2026-11-04T00:21:26Z",
      "native_id": "10.64898/2026.10.27.762172",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.10.27.762172v1"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "biorxiv:neuroscience",
      "subfield": "neuroscience"
    }
  ],
  "title": "Donor Aware Reanalysis of Neuronal Nuclei Supports STMN2 Depletion Associated with Nuclear TDP 43 loss in FTD and ALS",
  "title_text": "Donor Aware Reanalysis of Neuronal Nuclei Supports STMN2 Depletion Associated with Nuclear TDP 43 loss in FTD and ALS",
  "type": "preprint",
  "updated_at": "2026-11-05T00:20:50Z",
  "url": "https://research.draconitic.com/paper/bjrg9x9jy9mms",
  "venue": "bioRxiv",
  "versions": []
}