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Understanding the impact of 3XSNCA and its absence is crucial. This study investigates the differentiation of human induced pluripotent stem cell (hiPSC)-derived floor-plate progenitors into dopaminergic neurons. Three different genotypes were evaluated in this study: patient-derived hiPSCs with 3XSNCA, a gene-edited isogenic line with a frame-shift mutation on all SNCA alleles (SNCA 4KO), and a normal wild-type control. Our aim was to assess how the substantia nigra pars compacta (SNpc) microenvironment, damaged by 6-hydroxydopamine (6-OHDA), influences tyrosine hydroxylase-positive (Th+) neuron differentiation in these genetic variations. This study confirms successful in vitro differentiation into neuronal lineage in all cell lines. However, the SNCA 4KO line showed unusual LIM homeobox transcription factor 1 alpha (Lmx1a) extranuclear distribution. Crucially, both 3XSNCA and SNCA 4KO lines had reduced Th+ neuron expression, despite initial successful neuronal differentiation after two months post-transplantation. This indicates that while the SNpc environment supports early neuronal survival, SNCA gene alterations\u2014either amplification or knock-out\u2014negatively impact Th+ dopaminergic neuron maturation. These findings highlight SNCA\u2019s critical role in PD and underscore the value of hiPSC models in studying neurodegenerative diseases.<\/jats:p>","DOI":"10.3390\/life14060728","type":"journal-article","created":{"date-parts":[[2024,6,5]],"date-time":"2024-06-05T05:59:42Z","timestamp":1717567182000},"page":"728","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Alpha-Synuclein Gene Alterations Modulate Tyrosine Hydroxylase in Human iPSC-Derived Neurons in a Parkinson\u2019s Disease Animal Model"],"prefix":"10.3390","volume":"14","author":[{"given":"Luis Daniel","family":"Bernal-Conde","sequence":"first","affiliation":[{"name":"Laboratory of Regenerative Medicine, Physiology Department, Faculty of Medicine, National Autonomous University of Mexico, Mexico City 04510, Mexico"},{"name":"Molecular Neuropathology Department, Neuroscience Division, Institute of Cell Physiology, National Autonomous University of Mexico, Mexico City 04510, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ver\u00f3nica","family":"Pe\u00f1a-Mart\u00ednez","sequence":"additional","affiliation":[{"name":"Laboratory of Regenerative Medicine, Physiology Department, Faculty of Medicine, National Autonomous University of Mexico, Mexico City 04510, Mexico"},{"name":"Molecular Neuropathology Department, Neuroscience Division, Institute of Cell Physiology, National Autonomous University of Mexico, Mexico City 04510, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"C. Alejandra","family":"Morato-Torres","sequence":"additional","affiliation":[{"name":"Laboratory of Regenerative Medicine, Physiology Department, Faculty of Medicine, National Autonomous University of Mexico, Mexico City 04510, Mexico"},{"name":"Department of Pathology, Stanford University School of Medicine, Stanford, CA 94304, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rodrigo","family":"Ramos-Acevedo","sequence":"additional","affiliation":[{"name":"Laboratory of Regenerative Medicine, Physiology Department, Faculty of Medicine, National Autonomous University of Mexico, Mexico City 04510, Mexico"},{"name":"Molecular Neuropathology Department, Neuroscience Division, Institute of Cell Physiology, National Autonomous University of Mexico, Mexico City 04510, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9982-7571","authenticated-orcid":false,"given":"\u00d3scar","family":"Arias-Carri\u00f3n","sequence":"additional","affiliation":[{"name":"Movement and Sleep Disorders Unit, Dr. Manuel Gea Gonz\u00e1lez General Hospital, Mexico City 14080, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francisco J.","family":"Padilla-God\u00ednez","sequence":"additional","affiliation":[{"name":"Laboratory of Regenerative Medicine, Physiology Department, Faculty of Medicine, National Autonomous University of Mexico, Mexico City 04510, Mexico"},{"name":"Molecular Neuropathology Department, Neuroscience Division, Institute of Cell Physiology, National Autonomous University of Mexico, Mexico City 04510, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexa","family":"Delgado-Gonz\u00e1lez","sequence":"additional","affiliation":[{"name":"Laboratory of Regenerative Medicine, Physiology Department, Faculty of Medicine, National Autonomous University of Mexico, Mexico City 04510, Mexico"},{"name":"Molecular Neuropathology Department, Neuroscience Division, Institute of Cell Physiology, National Autonomous University of Mexico, Mexico City 04510, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marcela","family":"Palomero-Rivero","sequence":"additional","affiliation":[{"name":"Neurodevelopment and Physiology Department, Neuroscience Division, Institute of Cell Physiology, National Autonomous University of Mexico, Mexico City 04510, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Omar","family":"Collazo-Navarrete","sequence":"additional","affiliation":[{"name":"National Laboratory of Genomic Resources, Institute of Biomedical Research, National Autonomous University of Mexico, Mexico City 04510, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5013-3608","authenticated-orcid":false,"given":"Luis O.","family":"Soto-Rojas","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Pathogenesis, Laboratory 4, Building A4, Medical Surgeon Career, Faculty of Higher Studies Iztacala, National Autonomous University of Mexico, Mexico City 54090, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Margarita","family":"G\u00f3mez-Chavar\u00edn","sequence":"additional","affiliation":[{"name":"Laboratory of Regenerative Medicine, Physiology Department, Faculty of Medicine, National Autonomous University of Mexico, Mexico City 04510, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9952-5776","authenticated-orcid":false,"given":"Birgitt","family":"Sch\u00fcle","sequence":"additional","affiliation":[{"name":"Department of Pathology, Stanford University School of Medicine, Stanford, CA 94304, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Magdalena","family":"Guerra-Crespo","sequence":"additional","affiliation":[{"name":"Laboratory of Regenerative Medicine, Physiology Department, Faculty of Medicine, National Autonomous University of Mexico, Mexico City 04510, Mexico"},{"name":"Molecular Neuropathology Department, Neuroscience Division, Institute of Cell Physiology, National Autonomous University of Mexico, Mexico City 04510, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,6,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1111\/j.1460-9568.2009.06873.x","article-title":"The Second Brain and Parkinson\u2019s Disease","volume":"30","author":"Lebouvier","year":"2009","journal-title":"Eur. 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