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Here, a novel midbrain\u2013hindbrain\u2010assembloid model that recapitulates the spread of \u03b1\u2010synuclein pathology observed in PD patients, akin to Braak's hypothesis, is presented. Initially, the presence \u03b1\u2010synuclein pathology is demonstrated in the hindbrain organoids. Subsequently, sophisticated tissue engineering methods are employed to create midbrain\u2013hindbrain assembloids. These assembloids allow investigation and description of the spreading of \u03b1\u2010synuclein pathology, as it progresses from the hindbrain components to the midbrain regions within the integrated structure. It is observed that an increase in \u03b1\u2010synuclein in the hindbrain can induce transfer of the pathology into the healthy midbrain, as well as cause changes at the synapse level. The presented model constitutes a robust in vitro platform for investigating the mechanisms underlying \u03b1\u2010synuclein spreading and disease progression, and holding potential for the screening of prospective therapeutics targeting the pathological propagation in PD and related synucleinopathies.<\/jats:p>","DOI":"10.1002\/advs.202409040","type":"journal-article","created":{"date-parts":[[2025,4,26]],"date-time":"2025-04-26T08:30:16Z","timestamp":1745656216000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["\u03b1\u2010Synuclein Pathology Spreads in a Midbrain\u2013Hindbrain Assembloid Model"],"prefix":"10.1002","volume":"12","author":[{"given":"Gemma","family":"Gomez\u2010Giro","sequence":"first","affiliation":[{"name":"Developmental and Cellular Biology Luxembourg Centre for Systems Biomedicine University of Luxembourg  Belvaux L\u20104367 Luxembourg"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Frangenberg","sequence":"additional","affiliation":[{"name":"Developmental and Cellular Biology Luxembourg Centre for Systems Biomedicine University of Luxembourg  Belvaux L\u20104367 Luxembourg"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Vega","sequence":"additional","affiliation":[{"name":"Developmental and Cellular Biology Luxembourg Centre for Systems Biomedicine University of Luxembourg  Belvaux L\u20104367 Luxembourg"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alise","family":"Zagare","sequence":"additional","affiliation":[{"name":"Developmental and Cellular Biology Luxembourg Centre for Systems Biomedicine University of Luxembourg  Belvaux L\u20104367 Luxembourg"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyriaki","family":"Barmpa","sequence":"additional","affiliation":[{"name":"Developmental and Cellular Biology Luxembourg Centre for Systems Biomedicine University of Luxembourg  Belvaux L\u20104367 Luxembourg"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul M. 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