{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T21:32:51Z","timestamp":1793136771242,"version":"4.5.0"},"posted":{"date-parts":[[2026,5,24]]},"group-title":"Neuroscience","reference-count":115,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,5,24]],"date-time":"2026-05-24T00:00:00Z","timestamp":1779580800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"award":["R01 NS131660"],"award-info":[{"award-number":["R01 NS131660"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["T32 GM142607"],"award-info":[{"award-number":["T32 GM142607"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,5,24]]},"abstract":"<jats:title>Abstract\/Summary<\/jats:title>\n                <jats:p>\n                  Retroelements, including retrotransposons, endogenous retroviruses, and their fragments, as well as rare co-opted or domesticated retroelements, can contribute to neurodegenerative disorders and aging through modulation of gene expression and induction of neuroinflammation. Paternally Expressed Gene 10 (PEG10) is a retroelement-derived human gene that has recently been identified as a putative driver of Amyotrophic Lateral Sclerosis (ALS) and Angelman\u2019s Syndrome. PEG10 has been reported to bind nucleic acid and undergoes a complex self-processing pathway that results in gene expression changes when the protein accumulates in cells. Here, we report that PEG10 has selectivity for binding U\/G-rich RNAs and influences widespread gene expression changes. PEG10 overexpression mimics the loss of TDP-43 in broad changes to gene expression, including dysregulation of mRNA splicing pathways. Specific changes to mRNA splicing were largely unique between TDP-43 knockdown and PEG10 overexpression, as classic TDP-43 targets including\n                  <jats:italic>STMN2<\/jats:italic>\n                  were not altered by PEG10. Instead, we identified a unique role for PEG10 in regulating splicing of\n                  <jats:italic>neuregulin 3 (NRG3)<\/jats:italic>\n                  , a ligand for the neuronal receptor ERBB4. In SH-SY5Y cells and in human neurons overexpressing PEG10, NRG3 protein levels were decreased along cellular processes, suggesting that these cells are less competent at signaling through the NRG3\/ERBB4 axis. Using human patient data, we observed similar changes to\n                  <jats:italic>NRG3<\/jats:italic>\n                  splicing in\n                  <jats:italic>UBQLN2<\/jats:italic>\n                  -mediated ALS, where PEG10 is accumulated, as well as in some cases of sporadic ALS. In conclusion, the retroelement-derived gene PEG10 plays an unexpected role in regulating splicing of neuronal transcripts, which mimics some of the transcript changes observed in human ALS patient samples. Ultimately, this work has implications for the study of PEG10, and mRNA splicing in neurological diseases associated with elevated PEG10 abundance.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Highlights<\/jats:title>\n                  <jats:list list-type=\"bullet\">\n                    <jats:list-item>\n                      <jats:p>PEG10 NC expression influences abundance of transcripts implicated in ALS<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>\n                        PEG10 NC expression leads to an exon skipping event in\n                        <jats:italic>neuregulin 3 (NRG3)<\/jats:italic>\n                      <\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>NRG3 expression is decreased along dendrites of PEG10 NC expressing human neurons<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Expression of PEG10 NC mimics changes observed in human ALS<\/jats:p>\n                    <\/jats:list-item>\n                  <\/jats:list>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Graphical Abstract<\/jats:title>\n                  <jats:fig id=\"ufig1\" position=\"float\" fig-type=\"figure\" orientation=\"portrait\">\n                    <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"727000v1_ufig1\" position=\"float\" orientation=\"portrait\"\/>\n                  <\/jats:fig>\n                <\/jats:sec>","DOI":"10.64898\/2026.05.21.727000","type":"posted-content","created":{"date-parts":[[2026,5,24]],"date-time":"2026-05-24T23:25:12Z","timestamp":1779665112000},"source":"Crossref","is-referenced-by-count":1,"title":["The retroelement-derived human protein PEG10 is a regulator of mRNA splicing in 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