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Recent studies have shown that the loss of TDP-43 function leads to the inclusion of cryptic exons (CE) in several RNA transcript targets of TDP-43. Here, we show for the first time the detection of CEs in a single-nuclei RNA sequencing (snRNA-seq) dataset obtained from frontal and occipital cortices of\n                    <jats:italic>C9ORF72<\/jats:italic>\n                    patients that phenotypically span the ALS-FTD disease spectrum. We assessed each cellular cluster for detection of recently described TDP-43-induced CEs. Transcripts containing CEs in the genes\n                    <jats:italic>STMN2<\/jats:italic>\n                    and\n                    <jats:italic>KALRN<\/jats:italic>\n                    were detected in the frontal cortex of all\n                    <jats:italic>C9ORF72<\/jats:italic>\n                    disease groups with the highest frequency in excitatory neurons in the\n                    <jats:italic>C9ORF72<\/jats:italic>\n                    -FTD group. Within the excitatory neurons, the cluster with the highest proportion of cells containing a CE had transcriptomic similarities to von Economo neurons, which are known to be vulnerable to TDP-43 pathology and selectively lost in\n                    <jats:italic>C9ORF72<\/jats:italic>\n                    -FTD. Differential gene expression and pathway analysis of CE-containing neurons revealed multiple dysregulated metabolic processes. Our findings reveal novel insights into the transcriptomic changes of neurons vulnerable to TDP-43 pathology.\n                  <\/jats:p>","DOI":"10.1007\/s00401-023-02599-5","type":"journal-article","created":{"date-parts":[[2023,7,19]],"date-time":"2023-07-19T05:03:26Z","timestamp":1689743006000},"page":"433-450","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":68,"title":["Cryptic exon detection and transcriptomic changes revealed in single-nuclei RNA sequencing of C9ORF72 patients spanning the ALS-FTD spectrum"],"prefix":"10.1007","volume":"146","author":[{"given":"Lauren M.","family":"Gittings","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric B.","family":"Alsop","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jerry","family":"Antone","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mo","family":"Singer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy G.","family":"Whitsett","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rita","family":"Sattler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8833-6323","authenticated-orcid":false,"given":"Kendall","family":"Van Keuren-Jensen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,7,19]]},"reference":[{"key":"2599_CR1","doi-asserted-by":"publisher","DOI":"10.1002\/ctm2.818","volume":"12","author":"T Akiyama","year":"2022","unstructured":"Akiyama T, Koike Y, Petrucelli L, Gitler AD (2022) Cracking the cryptic code in amyotrophic lateral sclerosis and frontotemporal dementia: Towards therapeutic targets and biomarkers. 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