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Neuronal hyperexcitability occurs in the early stages of AD and experimental prion disease, prior to the onset of dementia, yet the underlying drivers are unclear. Here we identify an increase in the immediate early gene, Arc\/Arg3.1, in the human prion disease-affected frontal cortex, suggestive of neuronal hyperactivity. To investigate early signaling events initiated by prion aggregates (PrP\n                  <jats:sup>Sc<\/jats:sup>\n                  ) in human neurons, we stimulated PrP\n                  <jats:sup>C<\/jats:sup>\n                  in human iPSC-derived excitatory neurons (iNs) with a known PrP\n                  <jats:sup>Sc<\/jats:sup>\n                  -mimetic antibody (POM1), which recapitulated the Arc\/Arg3.1 response within two hours. Proteomics, RNAseq, and a phosphokinase array in iNs revealed alterations in the EGF receptor and increased phosphorylated phospholipase C (PLC)-\u03b31 (Y783), which was also observed in the cerebral cortex of prion-infected mice. Thus, PrP\n                  <jats:sup>C<\/jats:sup>\n                  ligands can induce a PLC-\u03b31 intracellular signaling cascade together with an Arc response, suggestive of a neuronal activity response.\n                <\/jats:p>","DOI":"10.1101\/2025.04.01.645054","type":"posted-content","created":{"date-parts":[[2025,4,5]],"date-time":"2025-04-05T20:05:12Z","timestamp":1743883512000},"source":"Crossref","is-referenced-by-count":0,"title":["PrP\n                  <sup>C<\/sup>\n                  -induced signaling in human neurons activates phospholipase C\u02631 and an Arc\/Arg3.1 response"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0722-2509","authenticated-orcid":false,"given":"Daniel","family":"Ojeda-Juarez","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gail","family":"Funk","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emily","family":"Richards","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexander J.","family":"Rajic","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0288-5645","authenticated-orcid":false,"given":"Daniel B.","family":"McClatchy","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katrin","family":"Soldau","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xu","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"suffix":"III","given":"John R.","family":"Yates","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Steven L.","family":"Gonias","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christina J.","family":"Sigurdson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2025040808400662000_2025.04.01.645054v1.1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.410300410"},{"key":"2025040808400662000_2025.04.01.645054v1.2","doi-asserted-by":"publisher","DOI":"10.1038\/s41398-022-02024-7"},{"key":"2025040808400662000_2025.04.01.645054v1.3","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2990.2000.026002143.x"},{"key":"2025040808400662000_2025.04.01.645054v1.4","doi-asserted-by":"publisher","DOI":"10.1097\/00001756-200101220-00043"},{"key":"2025040808400662000_2025.04.01.645054v1.5","doi-asserted-by":"publisher","DOI":"10.1046\/j.1460-9568.2003.02662.x"},{"key":"2025040808400662000_2025.04.01.645054v1.6","doi-asserted-by":"publisher","DOI":"10.1080\/14734220260418448"},{"key":"2025040808400662000_2025.04.01.645054v1.7","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2009.04.001"},{"key":"2025040808400662000_2025.04.01.645054v1.8","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2990.2000.00216.x"},{"key":"2025040808400662000_2025.04.01.645054v1.9","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0055004"},{"key":"2025040808400662000_2025.04.01.645054v1.10","doi-asserted-by":"crossref","unstructured":"Ojeda-Ju\u00e1rez D , Lawrence JA , Soldau K , Pizzo DP , Wheeler E , Aguilar-Calvo P , et al. 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