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Affected children present with either a severe form that does not respond to L\u2010Dopa treatment (THD\u2010B) or a milder L\u2010Dopa responsive form (THD\u2010A). We generated induced pluripotent stem cells (iPSCs) from THD patients that were differentiated into dopaminergic neurons (DAn) and compared with control\u2010DAn from healthy individuals and gene\u2010corrected isogenic controls. Consistent with patients, THD iPSC\u2010DAn displayed lower levels of DA metabolites and reduced TH expression, when compared to controls. Moreover, THD iPSC\u2010DAn showed abnormal morphology, including reduced total neurite length and neurite arborization defects, which were not evident in DAn differentiated from control\u2010iPSC. Treatment of THD\u2010iPSC\u2010DAn with L\u2010Dopa rescued the neuronal defects and disease phenotype only in THDA\u2010DAn. Interestingly, L\u2010Dopa treatment at the stage of neuronal precursors could prevent the alterations in THDB\u2010iPSC\u2010DAn, thus suggesting the existence of a critical developmental window in THD. Our iPSC\u2010based model recapitulates THD disease phenotypes and response to treatment, representing a promising tool for investigating pathogenic mechanisms, drug screening, and personalized management.<\/jats:p>","DOI":"10.15252\/emmm.202215847","type":"journal-article","created":{"date-parts":[[2023,2,6]],"date-time":"2023-02-06T03:12:56Z","timestamp":1675653176000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["iPSC\u2010based modeling of THD recapitulates disease phenotypes and reveals neuronal malformation"],"prefix":"10.1038","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0170-9762","authenticated-orcid":false,"given":"Alba","family":"Trist\u00e1n\u2010Noguero","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene","family":"Fern\u00e1ndez\u2010Carasa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carles","family":"Calatayud","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3715-8114","authenticated-orcid":false,"given":"Cristina","family":"Bermejo\u2010Casades\u00fas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0832-2963","authenticated-orcid":false,"given":"Meritxell","family":"Pons\u2010Espinal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arianna","family":"Colini Baldeschi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5778-5879","authenticated-orcid":false,"given":"Leticia","family":"Campa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesc","family":"Artigas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2069-9192","authenticated-orcid":false,"given":"Analia","family":"Bortolozzi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5115-194X","authenticated-orcid":false,"given":"Rosario","family":"Domingo\u2010Jim\u00e9nez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salvador","family":"Ib\u00e1\u00f1ez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6817-9807","authenticated-orcid":false,"given":"Merc\u00e8","family":"Pineda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3422-9685","authenticated-orcid":false,"given":"Rafael","family":"Artuch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2189-9775","authenticated-orcid":false,"given":"\u00c1ngel","family":"Raya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9853-688X","authenticated-orcid":false,"given":"\u00c0ngels","family":"Garc\u00eda\u2010Cazorla","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonella","family":"Consiglio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,2,6]]},"reference":[{"key":"BFEMMM202215847_CR1","doi-asserted-by":"crossref","first-page":"444","DOI":"10.1002\/jnr.10606","volume":"72","author":"S Althini","year":"2003","unstructured":"Althini S, Bengtsson H, Usoskin D, S\u00f6derstr\u00f6m S, Kylberg A, Lindqvist E, De Sousa Lopes SC, Olson L, Lindeberg J, Ebendal T (2003) Normal nigrostriatal innervation but dopamine dysfunction in mice carrying hypomorphic tyrosine hydroxylase alleles. 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