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The reasons why these neurons are selectively affected remain unclear. Here, to understand the unique molecular properties that may sensitize ETNs to ALS, we performed RNA sequencing of 79,169 single nuclei from cortices of patients and controls. In both patients and unaffected individuals, we found significantly higher expression of ALS risk genes in\n                    <jats:italic>THY1<\/jats:italic>\n                    <jats:sup>+<\/jats:sup>\n                    ETNs, regardless of diagnosis. In patients, this was accompanied by the induction of genes involved in protein homeostasis and stress responses that were significantly induced in a wide collection of ETNs. Examination of oligodendroglial and microglial nuclei revealed patient-specific downregulation of myelinating genes in oligodendrocytes and upregulation of an endolysosomal reactive state in microglia. Our findings suggest that selective vulnerability of extratelencephalic neurons is partly connected to their intrinsic molecular properties sensitizing them to genetics and mechanisms of degeneration.\n                  <\/jats:p>","DOI":"10.1038\/s43587-024-00640-0","type":"journal-article","created":{"date-parts":[[2024,6,21]],"date-time":"2024-06-21T06:07:00Z","timestamp":1718950020000},"page":"984-997","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":44,"title":["Single-nucleus sequencing reveals enriched expression of genetic risk factors in extratelencephalic neurons sensitive to degeneration in ALS"],"prefix":"10.1038","volume":"4","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2482-8801","authenticated-orcid":false,"given":"Francesco","family":"Limone","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8344-2140","authenticated-orcid":false,"given":"Daniel A.","family":"Mordes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Couto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9876-0021","authenticated-orcid":false,"given":"Brian J.","family":"Joseph","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jana M.","family":"Mitchell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3150-4052","authenticated-orcid":false,"given":"Martine","family":"Therrien","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1833-7296","authenticated-orcid":false,"given":"Sulagna Dia","family":"Ghosh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4720-9891","authenticated-orcid":false,"given":"Daniel","family":"Meyer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingying","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa","family":"Goldman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Bortolin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2043-1890","authenticated-orcid":false,"given":"Inma","family":"Cobos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beth","family":"Stevens","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6954-8184","authenticated-orcid":false,"given":"Steven A.","family":"McCarroll","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irena","family":"Kadiu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron","family":"Burberry","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olli","family":"Pietil\u00e4inen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin","family":"Eggan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,6,21]]},"reference":[{"key":"640_CR1","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1038\/nature20413","volume":"539","author":"JP Taylor","year":"2016","unstructured":"Taylor, J. P., Brown, R. H. Jr. & Cleveland, D. W. Decoding ALS: from genes to mechanism. Nature 539, 197\u2013206 (2016).","journal-title":"Nature"},{"key":"640_CR2","doi-asserted-by":"publisher","first-page":"162","DOI":"10.1056\/NEJMra1603471","volume":"377","author":"RH Brown","year":"2017","unstructured":"Brown, R. H. & Al-Chalabi, A. Amyotrophic lateral sclerosis. N. Engl. J. Med. 377, 162\u2013172 (2017).","journal-title":"N. Engl. J. Med."},{"key":"640_CR3","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1016\/j.stem.2021.12.008","volume":"29","author":"E Giacomelli","year":"2022","unstructured":"Giacomelli, E. et al. Human stem cell models of neurodegeneration: from basic science of amyotrophic lateral sclerosis to clinical translation. 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Postmortem cortex samples identify distinct molecular subtypes of ALS: retrotransposon activation, oxidative stress, and activated glia. Cell Rep. 29, 1164\u20131177 e1165 (2019).","journal-title":"Cell Rep."},{"key":"640_CR7","doi-asserted-by":"publisher","first-page":"150","DOI":"10.1038\/s41593-022-01205-3","volume":"26","author":"J Humphrey","year":"2023","unstructured":"Humphrey, J. et al. Integrative transcriptomic analysis of the amyotrophic lateral sclerosis spinal cord implicates glial activation and suggests new risk genes. Nat. Neurosci. 26, 150\u2013162 (2023).","journal-title":"Nat. Neurosci."},{"key":"640_CR8","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-35494-w","volume":"14","author":"J Eshima","year":"2023","unstructured":"Eshima, J. et al. Molecular subtypes of ALS are associated with differences in patient prognosis. Nat. Commun. 14, 95 (2023).","journal-title":"Nat. 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