{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T16:14:44Z","timestamp":1785428084733,"version":"3.56.0"},"posted":{"date-parts":[[2026,6,8]]},"group-title":"Neuroscience","reference-count":60,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T00:00:00Z","timestamp":1780876800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"award":["R01CA053840"],"award-info":[{"award-number":["R01CA053840"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["5P30CA045508"],"award-info":[{"award-number":["5P30CA045508"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"name":"CART"},{"name":"CSHL-Northwell Health Affiliation"},{"DOI":"10.13039\/100012434","name":"Irving A. Hansen Memorial Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100012434","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,6,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>Rett syndrome (RTT) is a severe neurodevelopmental disorder in which current therapeutic strategies remain largely focused on providing symptomatic relief without addressing underlying disease mechanisms. In contrast, we have identified the protein tyrosine phosphatase PTP1B as a mechanism-based therapeutic target and evaluated a class of selective, allosteric small-molecule inhibitors in female murine models of RTT. We show that one of these compounds localizes to brain regions central to motor coordination and cardio-respiratory control, which are core domains of RTT pathology. Pharmacological inhibition of PTP1B produces robust and sustained improvement in multiple disease symptoms, including muscle weakness, motor and coordination deficits, and cardiac and respiratory dysfunction. Concordant results obtained with genetic ablation of PTP1B, with effects maintained for over one year, demonstrate that phenotypic rescue arises from on-target modulation of disease-relevant signaling. Mechanistically, PTP1B inhibition is known to normalize neurotrophic and metabolic pathways, including TRKB and insulin\/leptin signaling, thereby restoring circuit-level function. These findings establish PTP1B as a clinically actionable, disease-modifying target and demonstrate that selective, allosteric inhibition of a protein tyrosine phosphatase can achieve durable therapeutic benefit in vivo. This work provides a strong rationale for the clinical evaluation of PTP1B inhibitors as a mechanism-based treatment strategy for RTT.<\/jats:p>\n                <jats:sec>\n                  <jats:title>One Sentence Summary<\/jats:title>\n                  <jats:p>We have validated inhibition of PTP1B as a mechanism-based therapeutic strategy that alleviates a wide range of symptoms in a mouse model of Rett syndrome.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.06.04.730096","type":"posted-content","created":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T18:35:15Z","timestamp":1780943715000},"source":"Crossref","is-referenced-by-count":0,"title":["Inhibition of protein tyrosine phosphatase PTP1B function ameliorates pathophysiological deficits in Rett Syndrome"],"prefix":"10.64898","author":[{"given":"Christopher A.","family":"Bonham","sequence":"first","affiliation":[{"name":"Cold Spring Harbor Laboratory; Cold Spring Harbor, NY 11724, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christy","family":"Felice","sequence":"additional","affiliation":[{"name":"Cold Spring Harbor Laboratory; Cold Spring Harbor, NY 11724, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa N.","family":"Christensen","sequence":"additional","affiliation":[{"name":"Cold Spring Harbor Laboratory; Cold Spring Harbor, NY 11724, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2394-1538","authenticated-orcid":false,"given":"Nicholas K.","family":"Tonks","sequence":"additional","affiliation":[{"name":"Cold Spring Harbor Laboratory; Cold Spring Harbor, NY 11724, 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