Evidence map›Paper›PMID 40783910›Full record

ArticleActa neuropathologica2025

Brain transcriptomics highlight abundant gene expression and splicing alterations in non-neuronal cells in aFTLD-U.

Sara Alidadiani, Júlia Faura, Sarah Wynants, Nele Peeters, Marleen Van den Broeck, Linus De Witte, Rafaela Policarpo, Simon Cheung, Cyril Pottier, Nikhil B Ghayal and 35 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Acta neuropathologica, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.

0numbers the graph read from it
0cells of the map it votes in
3citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

3 citing papers in PubMed.

  1. Article
  2. Review
  3. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

45 authors.

Sara AlidadianiDepartment of Biomedical Sciences, University of Antwerp, Building V 0.10, Universiteitsplein 1, 2610, Antwerp, Belgium.
Júlia FauraDepartment of Biomedical Sciences, University of Antwerp, Building V 0.10, Universiteitsplein 1, 2610, Antwerp, Belgium.
Sarah WynantsDepartment of Biomedical Sciences, University of Antwerp, Building V 0.10, Universiteitsplein 1, 2610, Antwerp, Belgium.
Nele PeetersDepartment of Biomedical Sciences, University of Antwerp, Building V 0.10, Universiteitsplein 1, 2610, Antwerp, Belgium.
Marleen Van den BroeckDepartment of Biomedical Sciences, University of Antwerp, Building V 0.10, Universiteitsplein 1, 2610, Antwerp, Belgium.
Linus De WitteDepartment of Biomedical Sciences, University of Antwerp, Building V 0.10, Universiteitsplein 1, 2610, Antwerp, Belgium.
Rafaela PolicarpoDepartment of Biomedical Sciences, University of Antwerp, Building V 0.10, Universiteitsplein 1, 2610, Antwerp, Belgium.
Simon CheungDepartment of Pathology, Vancouver Coastal Health, Vancouver, BC, Canada.
Cyril PottierDepartment of Biomedical Sciences, University of Antwerp, Building V 0.10, Universiteitsplein 1, 2610, Antwerp, Belgium.
Nikhil B GhayalDepartment of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
Merel O MolAlzheimer Center, Department of Neurology, Erasmus University Medical Center, Rotterdam, The Netherlands.
Marka van BlitterswijkDepartment of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
Evan UdineDepartment of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
Mariely DeJesus-HernandezDepartment of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
Matthew BakerDepartment of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
NiCole A FinchDepartment of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
Yan W AsmannDepartment of Quantitative Health Sciences, Mayo Clinic, Jacksonville, FL, USA.
Jeroen G J van RooijAlzheimer Center, Department of Neurology, Erasmus University Medical Center, Rotterdam, The Netherlands.
Aivi T NguyenDepartment of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
R Ross ReichardDepartment of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
Alissa L NanaDepartment of Neurology, UCSF Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA.
Oscar L LopezDepartment of Neurology, University of Pittsburgh, Pittsburg, PA, USA.
Adam L BoxerDepartment of Neurology, UCSF Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA.
Howard J RosenDepartment of Neurology, UCSF Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA.
Salvatore SpinaDepartment of Neurology, UCSF Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA.
Jochen HermsCenter for Neuropathology and Prion Research, University Hospital Munich, Ludwig-Maximilians-University, Munich, Germany.
Keith A JosephsDepartment of Neurology, Mayo Clinic, Rochester, MN, USA.
Ronald C PetersenDepartment of Neurology, Mayo Clinic, Rochester, MN, USA.
Robert A RissmanAlzheimer's Therapeutic Research Institute, Keck School of Medicine, University of Southern California, San Diego, CA, USA.
Annie HinikerDepartment of Pathology, University of California San Diego, La Jolla, CA, USA.
Lee-Cyn AngDepartment of Pathology and Laboratory Medicine, University of Western Ontario, London, ON, Canada.
Lea T GrinbergDepartment of Neurology, UCSF Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA.
Glenda M HallidayUniversity of Sydney, Sydney, Australia.
Bradley F BoeveDepartment of Neurology, Mayo Clinic, Rochester, MN, USA.
Neill R Graff-RadfordDepartment of Neurology, Mayo Clinic, Jacksonville, FL, USA.
Harro SeelaarAlzheimer Center, Department of Neurology, Erasmus University Medical Center, Rotterdam, The Netherlands.
Manuela NeumannMolecular Neuropathology of Neurodegenerative Diseases, DZNE Tuebingen, Tübingen, Germany.
Julia KoflerDepartment of Pathology, University of Pittsburgh, Pittsburg, PA, USA.
Charles L WhiteDivision of Neuropathology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
William W SeeleyDepartment of Neurology, UCSF Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA.
John C van SwietenAlzheimer Center, Department of Neurology, Erasmus University Medical Center, Rotterdam, The Netherlands.
Dennis W DicksonDepartment of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
Ian R A MackenzieDepartment of Pathology and Laboratory Medicine, University of British Columbia and Vancouver General Hospital, Vancouver, BC, Canada.
Wouter De CosterDepartment of Biomedical Sciences, University of Antwerp, Building V 0.10, Universiteitsplein 1, 2610, Antwerp, Belgium.
Rosa RademakersDepartment of Biomedical Sciences, University of Antwerp, Building V 0.10, Universiteitsplein 1, 2610, Antwerp, Belgium. rosa.rademakers@uantwerpen.vib.be.

Funding

Technology and Remote Assessment CoreU19AG063911 · NIA · MAYO CLINIC ROCHESTER · PI Bradley F Boeve · 2019 to 2026
$120.9M
TDP-43 Loss-of-Function: Biology to BiomarkersP01AG019724 · NIA · UNIVERSITY OF PENNSYLVANIA · PI Jennifer Merrilees · 2002 to 2026
$67.2M
Research Education ComponentP30AG062422 · NIA · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI Gil Dan Rabinovici · 2019 to 2026
$36.9M
Research Education ComponentP30AG066468 · NIA · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI C. Elizabeth Shaaban · 2020 to 2026
$29.4M
USCADRC Diversity Supplement PachicanoP30AG066530 · NIA · UNIVERSITY OF SOUTHERN CALIFORNIA · PI HELENA Chang CHUI, ARTHUR W TOGA · 2020 to 2026
$27.8M
PrPSc SPECIFIC INTERACTION WITH NOVEL PrP-Fc FUSION PROTEINSP50AG023501 · NIA · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI HUANG, YADONG · 2004 to 2018
$27.1M
Frontotemporal dementia and related disorders: transcriptomic profiling, biomarker discovery, and mechanistic insightR01NS121125 · NINDS · MAYO CLINIC JACKSONVILLE · PI GENDRON, TANIA FRANCE, VAN BLITTERSWIJK, MARKA · 2021 to 2025
$3.9M
Genetic Discovery and Pathobiology of Frontotemporal Lobar Degeneration and Related TDP-43 ProteinopathiesR35NS097261 · NINDS · MAYO CLINIC JACKSONVILLE · PI RADEMAKERS, ROSA · 2017 to 2019
$2.9M
C9orf72-mediated features, transcriptomic signatures, and translational studies for frontotemporal dementia and related disordersRF1NS123052 · NINDS · MAYO CLINIC JACKSONVILLE · PI VAN BLITTERSWIJK, MARKA · 2022 to 2022
$2.4M
C9orf72-mediated features transcriptomic signatures and translational studies for frontotemporal dementia and related disordersR01NS123052 · NINDS · MAYO CLINIC JACKSONVILLE · PI Marka Van Blitterswijk · 2025 to 2026
$1.3M
Uncovering RNA signatures of C9ORF72-linked ALS and related disordersR21NS110994 · NINDS · MAYO CLINIC JACKSONVILLE · PI VAN BLITTERSWIJK, MARKA · 2019 to 2019
$430k
CIHR 74580Fund for Scientific Research Flanders 12ASR24NNational Health and Medical Research Council of Australia Senior Leadership Fellowship 1176607National Institutes of Health,United States P30AG062422National Institutes of Health,United States P30AG066468National Institutes of Health,United States R21NS110994National Institutes of Health,United States R35NS097261National Institutes of Health,United States U19AG063911NIA NIH HHS P01 AG019724NIA NIH HHS P30 AG062422NIA NIH HHS P30 AG066468NIA NIH HHS P30 AG066530NIA NIH HHS P50 AG023501NIA NIH HHS U19 AG063911NINDS NIH HHS R01 NS121125NINDS NIH HHS R01 NS123052NINDS NIH HHS R21 NS110994NINDS NIH HHS R35 NS097261NINDS NIH HHS RF1 NS123052University of Antwerp DOCPRO4
6 · The paper itself

Abstract

Atypical frontotemporal lobar degeneration with ubiquitin-positive inclusions (aFTLD-U) is a rare cause of frontotemporal lobar degeneration (FTLD), characterized postmortem by neuronal inclusions of the FET family of proteins (FTLD-FET). The recent discovery of TAF15 amyloid filaments in aFTLD-U brains represents a significant step toward improved diagnostic and therapeutic strategies. However, our understanding of the etiology of this FTLD subtype remains limited, which severely hampers translational research efforts. To explore the transcriptomic changes in aFTLD-U, we performed bulk RNA sequencing on the frontal cortex tissue of 21 aFTLD-U patients and 20 control individuals. Cell-type deconvolution revealed loss of excitatory neurons and a higher proportion of astrocytes in aFTLD-U relative to controls. Differential gene expression and co-expression network analysis, adjusted for the shift in cell-type proportions, showed dysregulation of mitochondrial pathways, transcriptional regulators, and upregulation of the Sonic hedgehog (Shh) pathway, including the GLI1 transcription factor, in aFTLD-U. Overall, oligodendrocyte and astrocyte-enriched genes were significantly over-represented among the differentially expressed genes. Differential splicing analysis confirmed the dysregulation of non-neuronal cell types with significant splicing alterations, particularly in oligodendrocyte-enriched genes, including myelin basic protein (MBP), a crucial component of myelin. Immunohistochemistry in frontal cortex brain tissue also showed reduced myelin levels in aFTLD-U patients compared to controls. Together, these findings highlight a central role for glial cells, particularly astrocytes and oligodendrocytes, in the pathogenesis of aFTLD-U, with disruptions in mitochondrial activity, RNA metabolism, Shh signaling, and myelination as possible disease mechanisms. This study offers the first transcriptomic insight into aFTLD-U and presents new avenues for research into FTLD-FET.

Indexed as

BrainFrontotemporal Lobar DegenerationTranscriptomeAgedAstrocytesFemaleHumansMaleMiddle AgedNeuronsRNA SplicingaFTLD-UGlial cellsMitochondriaSonic hedgehog signalingSplicingTranscriptomics

Identifiers

PMID40783910
PMCPMC12336083

What OpenQuestion holds

Textmetadata
LicenceCC BY
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.