{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T00:02:58Z","timestamp":1785542578461,"version":"3.56.0"},"reference-count":55,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2025,11,14]],"date-time":"2025-11-14T00:00:00Z","timestamp":1763078400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"PRIN2022","award":["2022ZH5M72"],"award-info":[{"award-number":["2022ZH5M72"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Angelman Syndrome (AS) is a neurodevelopmental disorder caused by the deficiency of the UBE3A gene that for a E3 ligase protein part of the ubiquitin\u2013proteasome system (UPS). Autophagy and UPS systems remove abnormal proteins, but any dysfunction in these processes can affect neuronal development and wellbeing. Herein, the involvement of the UPS\/autophagy system in the regulation of intracellular signaling pathways related to toxic protein accumulation was investigated in cellular\/mice AS models, silenced for UB3A (UB3A\u2212). The main findings are as follows: (i) autophagy was upregulated in UBE3A\u2212 cells with respect to control cells; (ii) a dysregulation of the AKT\/mTOR pathway, linked to autophagy\/synaptic development, was evidenced in cellular\/animal models of AS with respect to controls; (iii) the ubiquitin ligase MDM2 was downregulated, and the tumor suppressor p53, normally inhibited by MDM2, enhanced its expression and transcriptional activity in UB3A\u2212 cells with respect to controls. Finally, UB3A\u2212 cells presented a significant alteration in the levels of \u03b2-amyloids with respect to control cells, and a reduction of \u03b1-synuclein levels, typical of neurodevelopmental disorder. Nevertheless, UB3A\u2212 cells do not show evident morphological abnormalities. Overall, these data suggest that AS models presented an altered signaling pathway related to autophagy\/UPS systems, potentially leading to the accumulation of toxic proteins affecting synaptic development.<\/jats:p>","DOI":"10.3390\/ijms262211032","type":"journal-article","created":{"date-parts":[[2025,11,14]],"date-time":"2025-11-14T11:49:43Z","timestamp":1763120983000},"page":"11032","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Dysfunction of the Autophagy System and MDM2\u2013p53 Axis Leads to the Accumulation of Amyloidogenic Proteins in Angelman Syndrome Models"],"prefix":"10.3390","volume":"26","author":[{"given":"Jacqueline F\u00e1tima","family":"Martins de Almeida","sequence":"first","affiliation":[{"name":"Department of Pharmacy, University of Pisa, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina","family":"Contestabile","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Pisa, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7323-2174","authenticated-orcid":false,"given":"Ilaria","family":"Tonazzini","sequence":"additional","affiliation":[{"name":"Istituto Nanoscienze, Consiglio Nazionale delle Ricerche (CNR)@NESTe, Piazza San Silvestro 12, 56127 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-2305-966X","authenticated-orcid":false,"given":"Chiara","family":"De Cesari","sequence":"additional","affiliation":[{"name":"Istituto Nanoscienze, Consiglio Nazionale delle Ricerche (CNR)@NESTe, Piazza San Silvestro 12, 56127 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6739-2860","authenticated-orcid":false,"given":"Laura","family":"Baroncelli","sequence":"additional","affiliation":[{"name":"Istituto Neuroscienze, CNR, Via Giuseppe Moruzzi 1, 56124 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9379-3027","authenticated-orcid":false,"given":"Claudia","family":"Martini","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Pisa, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7391-3087","authenticated-orcid":false,"given":"Simona","family":"Daniele","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Pisa, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1928","DOI":"10.17305\/bb.2025.11724","article-title":"Molecular aspects of Angelman Syndrome: Defining the new path forward","volume":"25","author":"Almeida","year":"2025","journal-title":"Biomol. 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