Donor Aware Reanalysis of Neuronal Nuclei Supports STMN2 Depletion Associated with Nuclear TDP 43 loss in FTD and ALS
- 1Tongji Medical College of Huazhong University of Science and Technology,
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.
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BibTeX
@misc{chaudhary2026donor,
title = {{Donor Aware Reanalysis of Neuronal Nuclei Supports STMN2 Depletion Associated with Nuclear TDP 43 loss in FTD and ALS}},
author = {A. CHAUDHARY and S. Yao},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.27.762172},
url = {https://www.biorxiv.org/content/10.64898/2026.10.27.762172v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Donor Aware Reanalysis of Neuronal Nuclei Supports STMN2 Depletion Associated with Nuclear TDP 43 loss in FTD and ALS
AU - A. CHAUDHARY
AU - S. Yao
PY - 2026
DA - 2026/10/27
PB - bioRxiv
DO - 10.64898/2026.10.27.762172
UR - https://www.biorxiv.org/content/10.64898/2026.10.27.762172v1
AB - 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.
ER -