TY  - JOUR
AU  - Alidadiani, Sara
AU  - Faura, Júlia
AU  - Wynants, Sarah
AU  - Peeters, Nele
AU  - Van den Broeck, Marleen
AU  - De Witte, Linus
AU  - Policarpo, Rafaela
AU  - Cheung, Simon
AU  - Pottier, Cyril
AU  - Ghayal, Nikhil B
AU  - Mol, Merel O
AU  - van Blitterswijk, Marka
AU  - Udine, Evan
AU  - DeJesus-Hernandez, Mariely
AU  - Baker, Matthew
AU  - Finch, NiCole A
AU  - Asmann, Yan W
AU  - van Rooij, Jeroen G J
AU  - Nguyen, Aivi T
AU  - Ross Reichard, R.
AU  - Nana, Alissa L
AU  - Lopez, Oscar L
AU  - Boxer, Adam L
AU  - Rosen, Howard J
AU  - Spina, Salvatore
AU  - Herms, Jochen
AU  - Josephs, Keith A
AU  - Petersen, Ronald C
AU  - Rissman, Robert A
AU  - Hiniker, Annie
AU  - Ang, Lee-Cyn
AU  - Grinberg, Lea T
AU  - Halliday, Glenda M
AU  - Boeve, Bradley F
AU  - Graff-Radford, Neill R
AU  - Seelaar, Harro
AU  - Neumann, Manuela
AU  - Kofler, Julia
AU  - White, Charles L
AU  - Seeley, William W
AU  - van Swieten, John C
AU  - Dickson, Dennis W
AU  - Mackenzie, Ian R A
AU  - De Coster, Wouter
AU  - Rademakers, Rosa
TI  - Brain transcriptomics highlight abundant gene expression and splicing alterations in non-neuronal cells in aFTLD-U.
JO  - Acta neuropathologica
VL  - 150
IS  - 1
SN  - 0001-6322
CY  - Heidelberg
PB  - Springer
M1  - DZNE-2025-00945
SP  - 17
PY  - 2025
AB  - 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.
KW  - Humans
KW  - Male
KW  - Female
KW  - Transcriptome
KW  - Aged
KW  - Frontotemporal Lobar Degeneration: genetics
KW  - Frontotemporal Lobar Degeneration: pathology
KW  - Frontotemporal Lobar Degeneration: metabolism
KW  - Middle Aged
KW  - Brain: metabolism
KW  - Brain: pathology
KW  - Neurons: metabolism
KW  - Neurons: pathology
KW  - RNA Splicing
KW  - Astrocytes: metabolism
KW  - Glial cells (Other)
KW  - Mitochondria (Other)
KW  - Sonic hedgehog signaling (Other)
KW  - Splicing (Other)
KW  - Transcriptomics (Other)
KW  - aFTLD-U (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:40783910
DO  - DOI:10.1007/s00401-025-02919-x
UR  - https://pub.dzne.de/record/280290
ER  -