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

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.

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Journal
Acta Neuropathologica
Published
2025-08-10
DOI
https://doi.org/10.1007/s00401-025-02919-x
Citations
2
Primary Topic
RNA Research and Splicing
Type
article
Field-Weighted Citation Impact
1.61

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article

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

Lea T. Grinberg, John Cornelis Van Swieten, Keith A. Josephs, Dennis W. Dickson et al.
2 citations
Acta Neuropathologica
RNA Research and Splicing
1.61
article

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

Lea T. Grinberg, John Cornelis Van Swieten, Keith A. Josephs, Dennis W. Dickson, Caroline Graff, Alissa L. Nana, Cyril P. Pottier, Robert A. Rissman, Marleen Van den Broeck, Linus De Witte, Nikhil B Ghayal, Yan W. Asmann, Charles L. White, Salvatore Spina, Nemo Peeters, Jeroen van Rooij, Merel O. Mol, Sarah Wynants, Glenda Margaret Halliday, Annie OF Hiniker, Julia Kofler, Harro Seelaar, Rafaela Policarpo, Ian R. Mackenzie, Aivi T. Nguyen, Matthew Baker, Bradley F. Boeve, Júlia Faura, Jochen Herms, Wouter De Coster, Howard J. Rosen, Marka van Blitterswijk, Robert Ross Reichard, Simon Cheung, Lee‐Cyn Ang, Manuela Neumann, Mariely DeJesus‐Hernandez, Oscar L. Lopez, Adam L. Boxer, Evan Udine, Ronald C. Petersen, Rosa Rademakers, NiCole A. Finch, William W. Seeley, Sara Alidadiani
article en
2 citations

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.

Acta NeuropathologicaVol. 150(1)
University of Southern California (US), Western University (CA), Autism Research Institute (US), The University of Sydney (AU), Vancouver Coastal Health (CA), University of British Columbia (CA), University of Antwerp (BE), University of California, San Francisco (US), Washington University in St. Louis (US), London Health Sciences Centre (CA), German Center for Neurodegenerative Diseases (DE), Erasmus MC (NL), WinnMed (US), Vancouver General Hospital (CA), University of California San Diego (US), Munich Cluster for Systems Neurology (DE), Mayo Clinic in Arizona (US), University Children's Hospital Tübingen (DE), VIB-UAntwerp Center for Molecular Neurology (BE), Mayo Clinic in Florida (US), Pittsburg State University (US), University of Tübingen (DE), Ludwig-Maximilians-Universität München (DE), The University of Texas Southwestern Medical Center (US)
Neuroscience Research Australia, Fonds Wetenschappelijk Onderzoek, Koning Boudewijnstichting, Universiteit Antwerpen, Vlaamse regering, National Institutes of Health, Canadian Institutes of Health Research, National Institute on Aging, National Institute of Neurological Disorders and Stroke
Openalex Percentile: Top 15%
RNA Research and Splicing
1.61
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