{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T14:35:41Z","timestamp":1782398141169,"version":"3.54.5"},"posted":{"date-parts":[[2024,6,4]]},"group-title":"Molecular Biology","reference-count":70,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,7,2]]},"abstract":"<jats:title>SUMMARY<\/jats:title>\n                <jats:p>\n                  Tuberous sclerosis complex (TSC) is an inherited neurodevelopmental disorder (NDD) with frequent manifestations of epilepsy and autism spectrum disorder (ASD). TSC is caused by inactivating mutations in\n                  <jats:italic>TSC1<\/jats:italic>\n                  or\n                  <jats:italic>TSC2<\/jats:italic>\n                  tumor suppressor genes, with encoded proteins hamartin (TSC1) and tuberin (TSC2) forming a functional complex inhibiting mechanistic target of rapamycin complex 1 (mTORC1) signaling. This has led to treatment with allosteric mTORC1 inhibitor rapamycin analogs (\u201crapalogs\u201d) for TSC tumors; however, rapalogs are ineffective for treating neurodevelopmental manifestations. mTORC1 signaling controls protein synthesis by regulating formation of the eIF4F complex, with further modulation by MNK1\/2 kinases via phosphorylation of the eIF4F subunit eIF4E. While both these pathways modulate translation, comparing their impact on transcriptome-wide mRNA translation, as well as effects of inhibiting these pathways in TSC has not been explored. Here, employing CRISPR-modified, isogenic TSC2 patient-derived neural progenitor cells (NPCs), we have examined transcriptome-wide changes in mRNA translation upon\n                  <jats:italic>TSC2<\/jats:italic>\n                  loss. Our results reveal dysregulated translation in\n                  <jats:italic>TSC2<\/jats:italic>\n                  -Null NPCs, which significantly overlaps with the translatome from\n                  <jats:italic>TSC1<\/jats:italic>\n                  -Null NPCs. Interestingly, numerous non-monogenic ASD-, NDD-and epilepsy-associated genes identified in patients harboring putative loss-of-function mutations, were translationally suppressed in\n                  <jats:italic>TSC2<\/jats:italic>\n                  -Null NPCs. Importantly, translation of these ASD- and NDD-associated genes was reversed upon inhibition of either mTORC1 or MNK1\/2 signaling using RMC-6272 or eFT-508, respectively. This study establishes the importance of mTORC1-eIF4F- and MNK-eIF4E-sensitive mRNA translation in TSC, ASD and other neurodevelopmental disorders laying the groundwork for evaluating drugs in clinical development that target these pathways as a treatment strategy for these disorders.\n                <\/jats:p>","DOI":"10.1101\/2024.06.04.597393","type":"posted-content","created":{"date-parts":[[2024,6,5]],"date-time":"2024-06-05T00:45:15Z","timestamp":1717548315000},"source":"Crossref","is-referenced-by-count":2,"title":["<i>TSC2<\/i>\n                  loss in neural progenitor cells suppresses translation of ASD\/NDD-associated transcripts in an mTORC1- and MNK1\/2-reversible fashion"],"prefix":"10.64898","author":[{"given":"Pauline","family":"Martin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krzysztof 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