{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T20:53:32Z","timestamp":1780606412565,"version":"3.54.1"},"reference-count":79,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,4,27]],"date-time":"2026-04-27T00:00:00Z","timestamp":1777248000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,4,27]],"date-time":"2026-04-27T00:00:00Z","timestamp":1777248000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100021856","name":"Ministero dell'Universit\u00e0 e della Ricerca","doi-asserted-by":"publisher","award":["Next Generation EU [DM 1557 11.10.2022]"],"award-info":[{"award-number":["Next Generation EU [DM 1557 11.10.2022]"]}],"id":[{"id":"10.13039\/501100021856","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100021856","name":"Ministero dell'Universit\u00e0 e della Ricerca","doi-asserted-by":"publisher","award":["PNRR Missione 4 \u201cIstruzione e Ricerca\u201d C2 Inve"],"award-info":[{"award-number":["PNRR Missione 4 \u201cIstruzione e Ricerca\u201d C2 Inve"]}],"id":[{"id":"10.13039\/501100021856","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100021856","name":"Ministero dell'Universit\u00e0 e della Ricerca","doi-asserted-by":"publisher","award":["No. IR0000009"],"award-info":[{"award-number":["No. IR0000009"]}],"id":[{"id":"10.13039\/501100021856","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100021856","name":"Ministero dell'Universit\u00e0 e della Ricerca","doi-asserted-by":"publisher","award":["MUR 3264\/20"],"award-info":[{"award-number":["MUR 3264\/20"]}],"id":[{"id":"10.13039\/501100021856","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["febs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FEBS Journal"],"abstract":"<jats:p>\n                    Juvenile Huntington's disease (jHD) is a severe genetic disorder with combined neurodegenerative and neurodevelopmental features, characterized by early onset and markedly reduced life expectancy. Despite extensive efforts, drug development has been largely unsuccessful and no effective therapy capable of mitigating the pathological phenotype is currently available. Here, we investigated the potential of the FDA\u2010approved drug iloperidone to ameliorate disease\u2010related phenotypes in cortical neurons differentiated from patient\u2010derived induced pluripotent stem cells. Given previous reports indicating that iloperidone can bind the Sigma 1 Receptor (S1R), we hypothesized that activation of S1R\u2010dependent proteostasis pathways could contribute to its potential therapeutic effects. Treatment with iloperidone in this human\u2010relevant model led to enhanced clearance of protein aggregates, improved neuronal survival, and activation of an adaptive unfolded protein response, consistent with engagement of proteostasis mechanisms. To test the hypothesis of S1R involvement and clarify the underlying molecular mechanisms, we combined cellular experiments with molecular dynamics simulations of S1R in its apo and ligand\u2010bound states and\n                    <jats:italic>in vitro<\/jats:italic>\n                    mass photometry experiments comparing iloperidone with PD144418, a well\u2010established antagonist. The simulations revealed distinct receptor conformations depending on the bound ligand: iloperidone induced specific conformational changes, whereas PD144418 behaved similarly to the apo receptor. Consistently, the two ligands exerted opposite effects on S1R oligomerization\n                    <jats:italic>in vitro<\/jats:italic>\n                    . Overall, the integration of experimental and computational data supports a model in which iloperidone behaves as an S1R agonist, promoting receptor dissociation and phenotypic recovery through modulation of proteostasis.\n                  <\/jats:p>","DOI":"10.1111\/febs.70563","type":"journal-article","created":{"date-parts":[[2026,4,27]],"date-time":"2026-04-27T09:26:55Z","timestamp":1777282015000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Iloperidone treatment mitigates the Juvenile Huntington's Disease phenotype possibly via Sigma\u20101 Receptor Modulation"],"prefix":"10.1111","author":[{"given":"Ersilia","family":"Fornetti","sequence":"first","affiliation":[{"name":"Departmental Faculty of Medicine UniCamillus\u2010Saint Camillus International University of Health Sciences  Rome Italy"},{"name":"CLN2S Center for Life Nano and Neuroscience, Italian Institute of Technology  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gaia","family":"Galluzzi","sequence":"additional","affiliation":[{"name":"CLN2S Center for Life Nano and Neuroscience, Italian Institute of Technology  Rome Italy"},{"name":"School of Advanced Studies University of Camerino  Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario","family":"Frezzini","sequence":"additional","affiliation":[{"name":"Department of Information Engineering, Computer Science and Mathematics University of L'Aquila  Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C\u00e9cile","family":"Exertier","sequence":"additional","affiliation":[{"name":"Institute of Molecular Biology and Pathology, Italian National Research Council (IBPM\u2010CNR)  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vittorio","family":"Brufani","sequence":"additional","affiliation":[{"name":"Institute of Molecular Biology and Pathology, Italian National Research Council (IBPM\u2010CNR)  Rome Italy"},{"name":"Department of Biochemical Sciences Sapienza University of Roma  Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gianni","family":"Colotti","sequence":"additional","affiliation":[{"name":"Institute of Molecular Biology and Pathology, Italian National Research Council (IBPM\u2010CNR)  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giancarlo","family":"Ruocco","sequence":"additional","affiliation":[{"name":"CLN2S Center for Life Nano and Neuroscience, Italian Institute of Technology  Rome Italy"},{"name":"Department of Physics Sapienza University of Rome  Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica","family":"Rosati","sequence":"additional","affiliation":[{"name":"Departmental Faculty of Medicine UniCamillus\u2010Saint Camillus International University of Health Sciences  Rome Italy"},{"name":"Cellular Reprogramming Unit, Fondazione IRCCS Casa Sollievo della Sofferenza  Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angelo Luigi","family":"Vescovi","sequence":"additional","affiliation":[{"name":"Faculty of Medicine Link Campus University  Rome Italy"},{"name":"Department of Neuroscience Abu Dhabi Stem Cell Center  Abu Dhabi UAE"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2731-6286","authenticated-orcid":false,"given":"Daniele","family":"Narzi","sequence":"additional","affiliation":[{"name":"Department of Physical and Chemical Sciences University of L'Aquila  Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1981-750X","authenticated-orcid":false,"given":"Ilaria","family":"Genovese","sequence":"additional","affiliation":[{"name":"Departmental Faculty of Medicine UniCamillus\u2010Saint Camillus International University of Health Sciences  Rome Italy"},{"name":"CLN2S Center for Life Nano and Neuroscience, Italian Institute of Technology  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7754-399X","authenticated-orcid":false,"given":"Andrea","family":"Ilari","sequence":"additional","affiliation":[{"name":"Institute of Molecular Biology and Pathology, Italian National Research Council (IBPM\u2010CNR)  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,4,27]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"crossref","first-page":"971","DOI":"10.1016\/0092-8674(93)90585-E","article-title":"A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes","volume":"72","author":"Macdonald M","year":"1993","journal-title":"Cell"},{"key":"e_1_2_11_3_1","doi-asserted-by":"crossref","DOI":"10.1371\/4f8606b742ef3","article-title":"The prevalence of juvenile Huntington's disease: a review of the 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