{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T04:59:27Z","timestamp":1785473967489,"version":"3.56.0"},"reference-count":29,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T00:00:00Z","timestamp":1785456000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Neurosci."],"abstract":"<jats:p>\n                    Sporadic Parkinson's disease (PD) is typically a late-onset disorder caused by a combination of genetics, environment, and aging, manifesting when the loss of midbrain dopaminergic neurons exceeds a critical threshold, usually after the age of 50. Conversely, early-onset PD, as observed in cases linked to\n                    <jats:italic>parkin (PRKN)<\/jats:italic>\n                    gene mutations, suggests mechanisms involving either accelerated postnatal neuron loss or an insufficient number of neurons at birth. Patients with the 22q11.2 deletion syndrome (DS) have a significantly higher prevalence of early-onset PD. The absence of known genes associated with hereditary PD in the deleted region suggests the involvement of novel, non-traditional risk factors. This could potentially implicate the neurodevelopmental origin of dopaminergic neurons arising from the floor plate. To investigate this hypothesis, we generated midbrain organoids from induced pluripotent stem cells derived from a patient with 22q11.2 DS. The organoids recapitulated key aspects of\n                    <jats:italic>in vivo<\/jats:italic>\n                    neurogenesis, revealing enhanced differentiation of dopaminergic neurons in 22q11.2DS- and\n                    <jats:italic>PRKN<\/jats:italic>\n                    -derived organoids compared to controls on days 28 and 56 of culture. These findings suggest that, in early-onset PD patients with 22q11.2 DS or\n                    <jats:italic>PRKN<\/jats:italic>\n                    mutation, enhanced neurogenesis could result in reduced number of dopaminergic neurons during early development. The organoids of early-onset PD demonstrated that progenitors undergo enhanced differentiation at an early stage. This suggests that the atypical developmental process could reduce progenitors before there are enough mature dopaminergic neurons. This in turn indicates that the onset of PD may occur as early as the embryonic stage.\n                  <\/jats:p>","DOI":"10.3389\/fncel.2026.1906023","type":"journal-article","created":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T04:25:10Z","timestamp":1785471910000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Neurogenesis defects in iPSC-derived midbrain organoids of early-onset Parkinson's disease with 22q11.2 deletion syndrome"],"prefix":"10.3389","volume":"20","author":[{"given":"Syugo","family":"Ueki","sequence":"first","affiliation":[{"name":"Department of Neurology, Kansai Medical University","place":["Hirakata, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshiya","family":"Kimura","sequence":"additional","affiliation":[{"name":"Department of iPS Cell Applied Medicine, Graduate School of Medicine, Kansai Medical University","place":["Hirakata, Osaka, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rie","family":"Tohge","sequence":"additional","affiliation":[{"name":"Department of Neurology, Kansai Medical University","place":["Hirakata, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atsushi","family":"Tamada","sequence":"additional","affiliation":[{"name":"Department of iPS Cell Applied Medicine, Graduate School of Medicine, Kansai Medical University","place":["Hirakata, Osaka, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mitsuaki","family":"Oki","sequence":"additional","affiliation":[{"name":"Department of Neurology, Kansai Medical University","place":["Hirakata, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yusuke","family":"Yakushiji","sequence":"additional","affiliation":[{"name":"Department of Neurology, Kansai Medical University","place":["Hirakata, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haruhisa","family":"Inoue","sequence":"additional","affiliation":[{"name":"iPSC-based Drug Discovery and Development Team, RIKEN BioResource Research Center (BRC)","place":["Kyoto, Japan"]},{"name":"Center for iPS Cell Research and Application (CiRA), Kyoto University","place":["Kyoto, Japan"]},{"name":"Medical-Risk Avoidance Based on iPS Cells Team, RIKEN Center for Advanced Intelligence Project (AIP)","place":["Kyoto, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satoshi","family":"Kaneko","sequence":"additional","affiliation":[{"name":"Department of Neurology, Kansai Medical University","place":["Hirakata, Japan"]},{"name":"Department Neurology, Medical Research Institute Kitano Hospital","place":["Osaka, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keiko","family":"Muguruma","sequence":"additional","affiliation":[{"name":"Department of iPS Cell Applied Medicine, Graduate School of Medicine, Kansai Medical University","place":["Hirakata, Osaka, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,31]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1039182","DOI":"10.3389\/fcell.2023.1039182","article-title":"Generation and characterization of NGLY1 patient-derived midbrain organoids","volume":"11","author":"Abbott","year":"2023","journal-title":"Front. 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