{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T10:13:09Z","timestamp":1790158389373,"version":"4.1.0"},"reference-count":54,"publisher":"Oxford University Press (OUP)","license":[{"start":{"date-parts":[[2026,3,6]],"date-time":"2026-03-06T00:00:00Z","timestamp":1772755200000},"content-version":"am","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003246","name":"Netherlands Organisation for Scientific Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003246","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Mechanisms of Dementia"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The semantic variant of primary progressive aphasia is a clinical subtype of frontotemporal lobar degeneration and is marked by TDP-43 subtype C pathology (FTLD-TDP C). It is a sporadic disease, yet has a strikingly homogeneous clinicopathological presentation, suggesting a common pathophysiology. The aim of this study was to discover dysregulated pathways in FTLD-TDP C through transcriptomics of the temporal cortex\u2014its most affected region.<\/jats:p>\n                  <jats:p>Bulk RNA sequencing was conducted on temporal cortices of a post-mortem cohort of 18 FTLD-TDP C patients and 23 sex- and age-matched controls. Differential expression and functional analyses were performed to identify differentially expressed genes [DEGs; false discovery rate (FDR) &amp;lt; 0.05] and functionally annotate them. We assessed the enrichment of TARDBP\u2019s protein interactors and RNA targets among the DEGs. Our findings were compared with other published RNA sequencing data on tauopathies (Alzheimer\u2019s dementia, progressive supranuclear palsy and FTLD with MAPT), FTLD-TDP (subtypes A and B) and available proteomics from this cohort. Additionally, we performed a weighted gene co-expression network analysis (WGCNA), adjusting for differences in cell type composition between cases and controls using cell deconvolution, and removing genes dysregulated in temporal cortices identified in other datasets. Among the FTLD-TDP DEGs, we focused on the enrichment of synaptic processes using SynGO.<\/jats:p>\n                  <jats:p>We found upregulation of (i) damage response, (ii) cell structure and (iii) RNA splicing processes, and (iv) downregulation of synaptic processes in 6322 DEGs and five disease-related WGCNA modules. TARDBP-related genes were enriched among the DEGs. Additionally, transmembrane transport across the neurovascular unit was dysregulated. After cell deconvolution and removal of common tau genes, postsynaptic processes remained dysregulated, specifically the gene ontology terms \u2018modulation of chemical synaptic transmission\u2019 and \u2018neurotransmitter receptor localization to postsynaptic specialization membrane\u2019. We found 11 synaptic FTLD-TDP C-specific genes affected at both the RNA and protein levels in the temporal cortex, which were involved in synaptic adhesion (CADM1, NCAN), signal transmission (COMT, RGS144, SLC1A2, TUBB2B) and synaptic plasticity (BEGAIN, ITPKA, LRFN1, RAB3B, SYNPO).<\/jats:p>\n                  <jats:p>In conclusion, a wide range of processes were dysregulated at the RNA level in the temporal cortex of FTLD-TDP C, including commonly affected processes in neurodegeneration, such as structural cell alterations. Dysregulation of TARDBP-related genes and RNA splicing has also been observed in other TDP-43 proteinopathies. Importantly, we found that postsynaptic processes were downregulated in FTLD-TDP C, after removing tauopathy-related genes and after cell deconvolution. In particular, the assembly of receptors at the postsynaptic membrane and synaptic signal transmission were affected, both at the RNA and protein levels. Future research on these pathways could elucidate distinct pathophysiological mechanisms and guide targeted clinical approaches.<\/jats:p>","DOI":"10.1093\/brain\/awag085","type":"journal-article","created":{"date-parts":[[2026,3,4]],"date-time":"2026-03-04T12:51:45Z","timestamp":1772628705000},"source":"Crossref","is-referenced-by-count":2,"title":["Transcriptomic signature of frontotemporal lobar degeneration with TDP-43 type C pathology"],"prefix":"10.1093","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-6399-8170","authenticated-orcid":false,"given":"Ana","family":"Rajicic","sequence":"first","affiliation":[{"name":"Department of Neurology and Alzheimer Center Erasmus MC, Erasmus University Medical Center , Rotterdam 3015 GD ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2533-2530","authenticated-orcid":false,"given":"Merel O","family":"Mol","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Erasmus University Medical Center , Rotterdam 3015 GD ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shamiram","family":"Melhem","sequence":"additional","affiliation":[{"name":"Department of Neurology and Alzheimer Center Erasmus MC, Erasmus University Medical Center , Rotterdam 3015 GD ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helena","family":"Kisic","sequence":"additional","affiliation":[{"name":"Department of Neurology and Alzheimer Center Erasmus MC, Erasmus University Medical Center , Rotterdam 3015 GD ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John C","family":"van Swieten","sequence":"additional","affiliation":[{"name":"Department of Neurology and Alzheimer Center Erasmus MC, Erasmus University Medical Center , Rotterdam 3015 GD ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1989-7527","authenticated-orcid":false,"given":"Harro","family":"Seelaar","sequence":"additional","affiliation":[{"name":"Department of Neurology and Alzheimer Center Erasmus MC, Erasmus University Medical Center , Rotterdam 3015 GD ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9754-073X","authenticated-orcid":false,"given":"Jeroen G J","family":"van Rooij","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Erasmus University Medical Center , Rotterdam 3015 GD ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,3,6]]},"reference":[{"key":"2026092305471197700_awag085-B1","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1001\/archneurol.2010.55","article-title":"What is semantic dementia? 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