{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T01:35:22Z","timestamp":1790904922922,"version":"4.1.0"},"reference-count":71,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2024,11,21]],"date-time":"2024-11-21T00:00:00Z","timestamp":1732147200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"PRIN","award":["2017228L3J"],"award-info":[{"award-number":["2017228L3J"]}]},{"DOI":"10.13039\/501100002803","name":"Fondazione Cariplo","doi-asserted-by":"publisher","award":["2015\u20131017"],"award-info":[{"award-number":["2015\u20131017"]}],"id":[{"id":"10.13039\/501100002803","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Italian Ministry of Health RRC"},{"DOI":"10.13039\/501100003196","name":"Italian Ministry of Health","doi-asserted-by":"publisher","award":["GR-2021-12372019"],"award-info":[{"award-number":["GR-2021-12372019"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003196","name":"Italian Ministry of Health","doi-asserted-by":"publisher","award":["PNRR-MAD-2022-12376035"],"award-info":[{"award-number":["PNRR-MAD-2022-12376035"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012264","name":"NIH","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100012264","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100023864","name":"NIA","doi-asserted-by":"publisher","award":["P30AG066512"],"award-info":[{"award-number":["P30AG066512"]}],"id":[{"id":"10.13039\/501100023864","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000049","name":"NIA","doi-asserted-by":"publisher","award":["P01AG060882"],"award-info":[{"award-number":["P01AG060882"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008591","name":"Fondazione Grigioni per il Morbo di Parkinson","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100008591","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Fresco Institute for Parkinson\u2019s and Movement Disorders"},{"name":"Dino Ferrari Center"},{"DOI":"10.13039\/100009578","name":"Mizutani Foundation for Glycoscience","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009578","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,4,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Fibrillary aggregation of \u03b1-synuclein in Lewy body inclusions and nigrostriatal dopaminergic neuron degeneration define Parkinson\u2019s disease neuropathology. Mutations in GBA1, encoding glucocerebrosidase, are the most frequent genetic risk factor for Parkinson\u2019s disease. However, the lack of reliable experimental models able to reproduce key neuropathological signatures has hampered clarification of the link between mutant glucocerebrosidase and Parkinson\u2019s disease pathology.<\/jats:p>\n                  <jats:p>Here, we describe an innovative protocol for the generation of human induced pluripotent stem cell-derived midbrain organoids containing dopaminergic neurons with nigral identity that reproduce characteristics of advanced maturation. When applied to patients with GBA1-related Parkinson\u2019s disease, this method enabled the differentiation of midbrain organoids recapitulating dopaminergic neuron loss and fundamental features of Lewy pathology observed in human brains, including the generation of \u03b1-synuclein fibrillary aggregates with seeding activity that also propagate pathology in healthy control organoids. Concurrently, we found that the retention of mutant glucocerebrosidase in the endoplasmic reticulum and increased levels of its substrate, glucosylceramide, are determinants of \u03b1-synuclein aggregation into Lewy body-like inclusions, and the reduction of glucocerebrosidase activity accelerated \u03b1-synuclein pathology by promoting fibrillary \u03b1-synuclein deposition.<\/jats:p>\n                  <jats:p>Finally, we demonstrated the efficacy of ambroxol and GZ667161 (two modulators of the glucocerebrosidase pathway in clinical development for the treatment of GBA1-related Parkinson\u2019s disease) in reducing \u03b1-synuclein pathology in this model, supporting the use of midbrain organoids as a relevant preclinical platform for investigational drug screening.<\/jats:p>","DOI":"10.1093\/brain\/awae365","type":"journal-article","created":{"date-parts":[[2024,11,19]],"date-time":"2024-11-19T23:30:09Z","timestamp":1732059009000},"page":"1242-1257","source":"Crossref","is-referenced-by-count":28,"title":["Lewy pathology formation in patient-derived\n                    <i>GBA1<\/i>\n                    Parkinson\u2019s disease midbrain organoids"],"prefix":"10.1093","volume":"148","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5375-2404","authenticated-orcid":false,"given":"Emanuele","family":"Frattini","sequence":"first","affiliation":[{"name":"Neurology Unit, IRCCS Foundation Ca\u2019 Granda Ospedale Maggiore Policlinico , Milan 20122 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gaia","family":"Faustini","sequence":"additional","affiliation":[{"name":"Department of Molecular and Translational Medicine, University of Brescia , Brescia 25123 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9262-1212","authenticated-orcid":false,"given":"Gianluca","family":"Lopez","sequence":"additional","affiliation":[{"name":"Division of Pathology, IRCCS Foundation Ca\u2019 Granda Ospedale Maggiore Policlinico, University of Milan , Milan 20122 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma Veronica","family":"Carsana","sequence":"additional","affiliation":[{"name":"Department of Medical Biotechnology and Translational Medicine, University of Milano , Milan 20054 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mattia","family":"Tosi","sequence":"additional","affiliation":[{"name":"Neurology Unit, IRCCS Foundation Ca\u2019 Granda Ospedale Maggiore Policlinico , Milan 20122 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