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

作者：Sara Alidadiani, Júlia Faura, Sarah Wynants, Nemo Peeters, Marleen Van den Broeck, Linus De Witte, Rafaela Policarpo, Simon Cheung, Cyril Pottier, Nikhil B Ghayal, Merel O. Mol, Marka van Blitterswijk, Evan Udine, Mariely DeJesus‐Hernandez, Matthew Baker, NiCole A. Finch, Yan W. Asmann, Jeroen van Rooij, Aivi T. Nguyen, R. Ross Reichard, Alissa L. Nana, Oscar L. Lopez, Adam L. Boxer, Howard J. Rosen, Salvatore Spina, Jochen Herms, Keith A. Josephs, Ronald C. Petersen, Robert A. Rissman, Annie Hiniker, Lee‐Cyn Ang, Lea T. Grinberg, Glenda M. Halliday, Bradley F. Boeve, Caroline Graff, Harro Seelaar, Manuela Neumann, Julia Kofler, Charles L. White, William W. Seeley, John C. van Swieten, Dennis W. Dickson, Ian R. Mackenzie, Wouter De Coster, Rosa Rademakers · 发表于：Acta Neuropathologica · 年份：2025 · DOI：10.1007/s00401-025-02919-x · 被引用次数：4 · 研究领域：RNA Research and Splicing、Mitochondrial Function and Pathology、RNA modifications and cancer

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. Immunohis...