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000280290 037__ $$aDZNE-2025-00945
000280290 041__ $$aEnglish
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000280290 1001_ $$aAlidadiani, Sara$$b0
000280290 245__ $$aBrain transcriptomics highlight abundant gene expression and splicing alterations in non-neuronal cells in aFTLD-U.
000280290 260__ $$aHeidelberg$$bSpringer$$c2025
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000280290 520__ $$aAtypical 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.
000280290 536__ $$0G:(DE-HGF)POF4-352$$a352 - Disease Mechanisms (POF4-352)$$cPOF4-352$$fPOF IV$$x0
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000280290 650_7 $$2Other$$aGlial cells
000280290 650_7 $$2Other$$aMitochondria
000280290 650_7 $$2Other$$aSonic hedgehog signaling
000280290 650_7 $$2Other$$aSplicing
000280290 650_7 $$2Other$$aTranscriptomics
000280290 650_7 $$2Other$$aaFTLD-U
000280290 650_2 $$2MeSH$$aHumans
000280290 650_2 $$2MeSH$$aMale
000280290 650_2 $$2MeSH$$aFemale
000280290 650_2 $$2MeSH$$aTranscriptome
000280290 650_2 $$2MeSH$$aAged
000280290 650_2 $$2MeSH$$aFrontotemporal Lobar Degeneration: genetics
000280290 650_2 $$2MeSH$$aFrontotemporal Lobar Degeneration: pathology
000280290 650_2 $$2MeSH$$aFrontotemporal Lobar Degeneration: metabolism
000280290 650_2 $$2MeSH$$aMiddle Aged
000280290 650_2 $$2MeSH$$aBrain: metabolism
000280290 650_2 $$2MeSH$$aBrain: pathology
000280290 650_2 $$2MeSH$$aNeurons: metabolism
000280290 650_2 $$2MeSH$$aNeurons: pathology
000280290 650_2 $$2MeSH$$aRNA Splicing
000280290 650_2 $$2MeSH$$aAstrocytes: metabolism
000280290 7001_ $$aFaura, Júlia$$b1
000280290 7001_ $$aWynants, Sarah$$b2
000280290 7001_ $$aPeeters, Nele$$b3
000280290 7001_ $$aVan den Broeck, Marleen$$b4
000280290 7001_ $$aDe Witte, Linus$$b5
000280290 7001_ $$aPolicarpo, Rafaela$$b6
000280290 7001_ $$aCheung, Simon$$b7
000280290 7001_ $$aPottier, Cyril$$b8
000280290 7001_ $$aGhayal, Nikhil B$$b9
000280290 7001_ $$aMol, Merel O$$b10
000280290 7001_ $$avan Blitterswijk, Marka$$b11
000280290 7001_ $$aUdine, Evan$$b12
000280290 7001_ $$aDeJesus-Hernandez, Mariely$$b13
000280290 7001_ $$aBaker, Matthew$$b14
000280290 7001_ $$aFinch, NiCole A$$b15
000280290 7001_ $$aAsmann, Yan W$$b16
000280290 7001_ $$avan Rooij, Jeroen G J$$b17
000280290 7001_ $$aNguyen, Aivi T$$b18
000280290 7001_ $$aRoss Reichard, R.$$b19
000280290 7001_ $$aNana, Alissa L$$b20
000280290 7001_ $$aLopez, Oscar L$$b21
000280290 7001_ $$aBoxer, Adam L$$b22
000280290 7001_ $$aRosen, Howard J$$b23
000280290 7001_ $$aSpina, Salvatore$$b24
000280290 7001_ $$0P:(DE-2719)2810441$$aHerms, Jochen$$b25$$udzne
000280290 7001_ $$aJosephs, Keith A$$b26
000280290 7001_ $$aPetersen, Ronald C$$b27
000280290 7001_ $$aRissman, Robert A$$b28
000280290 7001_ $$aHiniker, Annie$$b29
000280290 7001_ $$aAng, Lee-Cyn$$b30
000280290 7001_ $$aGrinberg, Lea T$$b31
000280290 7001_ $$aHalliday, Glenda M$$b32
000280290 7001_ $$aBoeve, Bradley F$$b33
000280290 7001_ $$aGraff-Radford, Neill R$$b34
000280290 7001_ $$aSeelaar, Harro$$b35
000280290 7001_ $$0P:(DE-2719)2810592$$aNeumann, Manuela$$b36$$udzne
000280290 7001_ $$aKofler, Julia$$b37
000280290 7001_ $$aWhite, Charles L$$b38
000280290 7001_ $$aSeeley, William W$$b39
000280290 7001_ $$avan Swieten, John C$$b40
000280290 7001_ $$aDickson, Dennis W$$b41
000280290 7001_ $$aMackenzie, Ian R A$$b42
000280290 7001_ $$aDe Coster, Wouter$$b43
000280290 7001_ $$aRademakers, Rosa$$b44
000280290 773__ $$0PERI:(DE-600)1458410-4$$a10.1007/s00401-025-02919-x$$gVol. 150, no. 1, p. 17$$n1$$p17$$tActa neuropathologica$$v150$$x0001-6322$$y2025
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