Journal Article

DZNE-2025-00945

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Brain transcriptomics highlight abundant gene expression and splicing alterations in non-neuronal cells in aFTLD-U.

Alidadiani, S. ; Faura, J. ; Wynants, S. ; Peeters, N. ; Van den Broeck, M. ; De Witte, L. ; Policarpo, R. ; Cheung, S. ; Pottier, C. ; Ghayal, N. B. ; Mol, M. O. ; van Blitterswijk, M. ; Udine, E. ; DeJesus-Hernandez, M. ; Baker, M. ; Finch, N. A. ; Asmann, Y. W. ; van Rooij, J. G. J. ; Nguyen, A. T. ; Ross Reichard, R. ; Nana, A. L. ; Lopez, O. L. ; Boxer, A. L. ; Rosen, H. J. ; Spina, S. ; Herms, J.DZNE* ; Josephs, K. A. ; Petersen, R. C. ; Rissman, R. A. ; Hiniker, A. ; Ang, L.-C. ; Grinberg, L. T. ; Halliday, G. M. ; Boeve, B. F. ; Graff-Radford, N. R. ; Seelaar, H. ; Neumann, M.DZNE* ; Kofler, J. ; White, C. L. ; Seeley, W. W. ; van Swieten, J. C. ; Dickson, D. W. ; Mackenzie, I. R. A. ; De Coster, W. ; Rademakers, R.

2025
Springer Heidelberg

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Please use a persistent id in citations: doi:10.1007/s00401-025-02919-x

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.

Keyword(s): Humans (MeSH) ; Male (MeSH) ; Female (MeSH) ; Transcriptome (MeSH) ; Aged (MeSH) ; Frontotemporal Lobar Degeneration: genetics (MeSH) ; Frontotemporal Lobar Degeneration: pathology (MeSH) ; Frontotemporal Lobar Degeneration: metabolism (MeSH) ; Middle Aged (MeSH) ; Brain: metabolism (MeSH) ; Brain: pathology (MeSH) ; Neurons: metabolism (MeSH) ; Neurons: pathology (MeSH) ; RNA Splicing (MeSH) ; Astrocytes: metabolism (MeSH) ; Glial cells ; Mitochondria ; Sonic hedgehog signaling ; Splicing ; Transcriptomics ; aFTLD-U

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Contributing Institute(s):

1. Translational Brain Research (AG Herms)
2. Molecular Neuropathology of Neurodegenerative Diseases (AG Neumann)

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)

Appears in the scientific report 2025

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Database coverage:
; ; ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; DEAL Springer ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 10 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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