{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T17:22:01Z","timestamp":1793726521332,"version":"4.6.1"},"reference-count":85,"publisher":"Springer Science and Business Media LLC","issue":"10","license":[{"start":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T00:00:00Z","timestamp":1781654400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T00:00:00Z","timestamp":1781654400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100010661","name":"EC | Horizon 2020 Framework Programme","doi-asserted-by":"publisher","award":["#101003329"],"award-info":[{"award-number":["#101003329"]}],"id":[{"id":"10.13039\/100010661","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010661","name":"EC | Horizon 2020 Framework Programme","doi-asserted-by":"publisher","award":["#101003329"],"award-info":[{"award-number":["#101003329"]}],"id":[{"id":"10.13039\/100010661","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010661","name":"EC | Horizon 2020 Framework Programme","doi-asserted-by":"publisher","award":["101003329"],"award-info":[{"award-number":["101003329"]}],"id":[{"id":"10.13039\/100010661","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010661","name":"EC | Horizon 2020 Framework Programme","doi-asserted-by":"publisher","award":["101003329"],"award-info":[{"award-number":["101003329"]}],"id":[{"id":"10.13039\/100010661","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010661","name":"EC | Horizon 2020 Framework Programme","doi-asserted-by":"publisher","award":["101003329"],"award-info":[{"award-number":["101003329"]}],"id":[{"id":"10.13039\/100010661","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000864","name":"Michael J. Fox Foundation for Parkinson&apos;s Research","doi-asserted-by":"publisher","award":["ASAP-000420"],"award-info":[{"award-number":["ASAP-000420"]}],"id":[{"id":"10.13039\/100000864","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000864","name":"Michael J. Fox Foundation for Parkinson&apos;s Research","doi-asserted-by":"publisher","award":["ASAP-000420"],"award-info":[{"award-number":["ASAP-000420"]}],"id":[{"id":"10.13039\/100000864","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000864","name":"Michael J. Fox Foundation for Parkinson&apos;s Research","doi-asserted-by":"publisher","award":["ASAP-000420"],"award-info":[{"award-number":["ASAP-000420"]}],"id":[{"id":"10.13039\/100000864","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000864","name":"Michael J. Fox Foundation for Parkinson&apos;s Research","doi-asserted-by":"publisher","award":["ASAP-000420"],"award-info":[{"award-number":["ASAP-000420"]}],"id":[{"id":"10.13039\/100000864","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000864","name":"Michael J. Fox Foundation for Parkinson&apos;s Research","doi-asserted-by":"publisher","award":["ASAP-000420"],"award-info":[{"award-number":["ASAP-000420"]}],"id":[{"id":"10.13039\/100000864","id-type":"DOI","asserted-by":"publisher"}]},{"name":"HR was supported by an UPC BIosPC scholarship (contrats doctoraux d\u2019\u00e9tat #D25ZNWDC)."}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Mol Psychiatry"],"published-print":{"date-parts":[[2026,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Human midbrain organoids (hMOs) derived from induced pluripotent stem cells provide a powerful system to model disorders involving dopamine (DA) dysfunction, including Parkinson\u2019s disease (PD) and neuropsychiatric conditions. However, current differentiation protocols still fall short in recapitulating early specification, substantia nigra pars compacta (SNpc)-like identity, and the functional maturation of vulnerable DA neurons. Here, we established a differentiation strategy that combines tri-phasic WNT modulation with dynamic bioreactor culture to generate hMOs enriched in SNpc-like DA neurons. This approach significantly increases the yield of TH\u207a\/GIRK2\u207a and TH\u207a\/ALDH1A1\u207a DA neurons and promotes enhanced synaptic maturation, robust electrophysiological activity, and elevated DA release. Single-cell transcriptomics revealed that this strategy drives the emergence of\n                    <jats:italic>SOX6<\/jats:italic>\n                    <jats:sup>+<\/jats:sup>\n                    \/\n                    <jats:italic>GIRK2<\/jats:italic>\n                    <jats:sup>+<\/jats:sup>\n                    SNpc-like neurons, accompanied by upregulation of synaptic, metabolic, and maturation programs, alongside reduced cell stress and apoptotic signaling. Importantly, hMOs demonstrated vulnerability upon exposure to \u03b1-synuclein preformed fibrils, resulting in aggregate formation and DA neuron degeneration, supporting their use as a human model of PD-relevant pathology. Overall, this system provides a scalable and physiologically relevant approach to investigate molecular mechanisms underlying neurodegeneration and DA-related disorders.\n                  <\/jats:p>","DOI":"10.1038\/s41380-026-03667-4","type":"journal-article","created":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T18:49:18Z","timestamp":1781722158000},"page":"5900-5916","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Engineering functional ventral midbrain dopaminergic neurons in human organoids through WNT modulation and bioreactor culture"],"prefix":"10.1038","volume":"31","author":[{"given":"Hariam","family":"Raji","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federico","family":"Bertoli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8842-4286","authenticated-orcid":false,"given":"Maria Jose","family":"Perez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alicia","family":"Lam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Volpicelli-Daley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michela","family":"Deleidi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,17]]},"reference":[{"key":"3667_CR1","doi-asserted-by":"publisher","first-page":"373","DOI":"10.1038\/nature12517","volume":"501","author":"MA Lancaster","year":"2013","unstructured":"Lancaster MA, Renner M, Martin CA, Wenzel D, Bicknell LS, Hurles ME, et al. Cerebral organoids model human brain development and microcephaly. Nature. 2013;501:373\u20139.","journal-title":"Nature"},{"key":"3667_CR2","doi-asserted-by":"publisher","first-page":"671","DOI":"10.1038\/nmeth.3415","volume":"12","author":"AM Pasca","year":"2015","unstructured":"Pasca AM, Sloan SA, Clarke LE, Tian Y, Makinson CD, Huber N, et al. Functional cortical neurons and astrocytes from human pluripotent stem cells in 3D culture. Nat Methods. 2015;12:671\u20138.","journal-title":"Nat Methods"},{"key":"3667_CR3","doi-asserted-by":"publisher","first-page":"565","DOI":"10.1038\/nprot.2017.152","volume":"13","author":"X Qian","year":"2018","unstructured":"Qian X, Jacob F, Song MM, Nguyen HN, Song H, Ming G-l. Generation of human brain region\u2013specific organoids using a miniaturized spinning bioreactor. Nature Protocols. 2018;13:565\u201380.","journal-title":"Nature Protocols"},{"key":"3667_CR4","doi-asserted-by":"publisher","first-page":"573","DOI":"10.1038\/nrn.2017.107","volume":"18","author":"E Di Lullo","year":"2017","unstructured":"Di Lullo E, Kriegstein AR. The use of brain organoids to investigate neural development and disease. Nat Rev Neurosci. 2017;18:573\u201384.","journal-title":"Nat Rev Neurosci"},{"key":"3667_CR5","doi-asserted-by":"publisher","first-page":"523","DOI":"10.1038\/s41586-019-1289-x","volume":"570","author":"S Velasco","year":"2019","unstructured":"Velasco S, Kedaigle AJ, Simmons SK, Nash A, Rocha M, Quadrato G, et al. Individual brain organoids reproducibly form cell diversity of the human cerebral cortex. Nature. 2019;570:523\u20137.","journal-title":"Nature"},{"key":"3667_CR6","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1007\/5584_2021_647","volume":"1347","author":"D Sagrac","year":"2021","unstructured":"Sagrac D, Sisli HB, Senkal S, Hayal TB, Sahin F, Dogan A. Organoids in Tissue Transplantation. Adv Exp Med Biol. 2021;1347:45\u201364.","journal-title":"Adv Exp Med Biol"},{"key":"3667_CR7","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-37454-4","volume":"14","author":"P Baden","year":"2023","unstructured":"Baden P, Perez MJ, Raji H, Bertoli F, Kalb S, Illescas M, et al. Glucocerebrosidase is imported into mitochondria and preserves complex I integrity and energy metabolism. Nature Communications. 2023;14:1930.","journal-title":"Nature Communications"},{"key":"3667_CR8","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1038\/s41531-019-0078-4","volume":"5","author":"LM Smits","year":"2019","unstructured":"Smits LM, Reinhardt L, Reinhardt P, Glatza M, Monzel AS, Stanslowsky N, et al. Modeling Parkinson\u2019s disease in midbrain-like organoids. NPJ Parkinsons Dis. 2019;5:5.","journal-title":"NPJ Parkinsons Dis"},{"key":"3667_CR9","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1002\/(SICI)1096-9861(19960101)364:1<121::AID-CNE11>3.0.CO;2-1","volume":"364","author":"DA McRitchie","year":"1996","unstructured":"McRitchie DA, Hardman CD, Halliday GM. Cytoarchitectural distribution of calcium binding proteins in midbrain dopaminergic regions of rats and humans. J Comp Neurol. 1996;364:121\u201350.","journal-title":"J Comp Neurol"},{"key":"3667_CR10","doi-asserted-by":"publisher","first-page":"1709","DOI":"10.1093\/hmg\/ddi178","volume":"14","author":"CY Chung","year":"2005","unstructured":"Chung CY, Seo H, Sonntag KC, Brooks A, Lin L, Isacson O. Cell type-specific gene expression of midbrain dopaminergic neurons reveals molecules involved in their vulnerability and protection. Hum Mol Genet. 2005;14:1709\u201325.","journal-title":"Hum Mol Genet"},{"key":"3667_CR11","doi-asserted-by":"publisher","first-page":"1437","DOI":"10.1093\/brain\/122.8.1437","volume":"122","author":"P Damier","year":"1999","unstructured":"Damier P, Hirsch EC, Agid Y, Graybiel AM. The substantia nigra of the human brain. II. Patterns of loss of dopamine-containing neurons in Parkinson\u2019s disease. Brain. 1999;122:1437\u201348.","journal-title":"Brain"},{"key":"3667_CR12","doi-asserted-by":"publisher","first-page":"345","DOI":"10.1038\/334345a0","volume":"334","author":"E Hirsch","year":"1988","unstructured":"Hirsch E, Graybiel AM, Agid YA. Melanized dopaminergic neurons are differentially susceptible to degeneration in Parkinson\u2019s disease. Nature. 1988;334:345\u20138.","journal-title":"Nature"},{"key":"3667_CR13","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1093\/jmcb\/mjt043","volume":"6","author":"M Joksimovic","year":"2014","unstructured":"Joksimovic M, Awatramani R. Wnt\/\u03b2-catenin signaling in midbrain dopaminergic neuron specification and differentiation. J Mol Cell Biol. 2014;6:27\u201333.","journal-title":"J Mol Cell Biol"},{"key":"3667_CR14","doi-asserted-by":"publisher","first-page":"12413","DOI":"10.1523\/JNEUROSCI.1077-11.2011","volume":"31","author":"CH Yan","year":"2011","unstructured":"Yan CH, Levesque M, Claxton S, Johnson RL, Ang SL. Lmx1a and lmx1b function cooperatively to regulate proliferation, specification, and differentiation of midbrain dopaminergic progenitors. J Neurosci. 2011;31:12413\u201325.","journal-title":"J Neurosci"},{"key":"3667_CR15","doi-asserted-by":"publisher","first-page":"2718","DOI":"10.1016\/j.stemcr.2021.09.014","volume":"16","author":"T Oosterveen","year":"2021","unstructured":"Oosterveen T, Gar\u00e7\u00e3o P, Moles-Garcia E, Soleilhavoup C, Travaglio M, Sheraz S, et al. Pluripotent stem cell derived dopaminergic subpopulations model the selective neuron degeneration in Parkinson\u2019s disease. Stem Cell Reports. 2021;16:2718\u201335.","journal-title":"Stem Cell Reports"},{"key":"3667_CR16","doi-asserted-by":"publisher","first-page":"343","DOI":"10.1016\/j.stem.2021.01.005","volume":"28","author":"TW Kim","year":"2021","unstructured":"Kim TW, Piao J, Koo SY, Kriks S, Chung SY, Betel D, et al. Biphasic activation of WNT signaling facilitates the derivation of midbrain dopamine neurons from hESCs for translational use. Cell Stem Cell. 2021;28:343\u201355.e345.","journal-title":"Cell Stem Cell"},{"key":"3667_CR17","doi-asserted-by":"publisher","first-page":"393","DOI":"10.1016\/j.cell.2005.10.037","volume":"124","author":"E Andersson","year":"2006","unstructured":"Andersson E, Tryggvason U, Deng Q, Friling S, Alekseenko Z, Robert B, et al. Identification of intrinsic determinants of midbrain dopamine neurons. Cell. 2006;124:393\u2013405.","journal-title":"Cell"},{"key":"3667_CR18","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1093\/jmcb\/mju001","volume":"6","author":"E Arenas","year":"2014","unstructured":"Arenas E. Wnt signaling in midbrain dopaminergic neuron development and regenerative medicine for Parkinson\u2019s disease. J Mol Cell Biol. 2014;6:42\u201353.","journal-title":"J Mol Cell Biol"},{"key":"3667_CR19","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2025.115216","volume":"388","author":"Z Li","year":"2025","unstructured":"Li Z, Duan J, Cao A, Gong Z, Liu H, Shen D, et al. Activating Wnt1\/beta-Catenin signaling pathway to restore Otx2 expression in the dopaminergic neurons of ventral midbrain. Exp Neurol. 2025;388:115216.","journal-title":"Exp Neurol"},{"key":"3667_CR20","doi-asserted-by":"publisher","first-page":"5170","DOI":"10.1523\/JNEUROSCI.5569-08.2009","volume":"29","author":"M Yin","year":"2009","unstructured":"Yin M, Liu S, Yin Y, Li S, Li Z, Wu X, et al. Ventral mesencephalon-enriched genes that regulate the development of dopaminergic neurons in vivo. J Neurosci. 2009;29:5170\u201382.","journal-title":"J Neurosci"},{"key":"3667_CR21","doi-asserted-by":"publisher","first-page":"566","DOI":"10.1016\/j.cell.2016.09.027","volume":"167","author":"G La Manno","year":"2016","unstructured":"La Manno G, Gyllborg D, Codeluppi S, Nishimura K, Salto C, Zeisel A, et al. Molecular diversity of midbrain development in mouse, human, and stem cells. Cell. 2016;167:566\u201380.e519.","journal-title":"Cell"},{"key":"3667_CR22","doi-asserted-by":"publisher","first-page":"588","DOI":"10.1038\/s41593-022-01061-1","volume":"25","author":"T Kamath","year":"2022","unstructured":"Kamath T, Abdulraouf A, Burris SJ, Langlieb J, Gazestani V, Nadaf NM, et al. Single-cell genomic profiling of human dopamine neurons identifies a population that selectively degenerates in Parkinson\u2019s disease. Nat Neurosci. 2022;25:588\u201395.","journal-title":"Nat Neurosci"},{"key":"3667_CR23","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-16225-5","volume":"11","author":"K Tiklova","year":"2020","unstructured":"Tiklova K, Nolbrant S, Fiorenzano A, Bjorklund AK, Sharma Y, Heuer A, et al. Single cell transcriptomics identifies stem cell-derived graft composition in a model of Parkinson\u2019s disease. Nat Commun. 2020;11:2434.","journal-title":"Nat Commun"},{"key":"3667_CR24","doi-asserted-by":"publisher","DOI":"10.1016\/j.crmeth.2024.100779","volume":"4","author":"PN Nwokoye","year":"2024","unstructured":"Nwokoye PN, Abilez OJ. Bioengineering methods for vascularizing organoids. Cell Rep Methods. 2024;4:100779.","journal-title":"Cell Rep Methods"},{"key":"3667_CR25","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2022.826193","volume":"16","author":"A Ni","year":"2022","unstructured":"Ni A, Ernst C. Evidence that substantia nigra pars compacta dopaminergic neurons are selectively vulnerable to oxidative stress because they are highly metabolically active. Front Cell Neurosci. 2022;16:826193.","journal-title":"Front Cell Neurosci"},{"key":"3667_CR26","doi-asserted-by":"publisher","first-page":"2349","DOI":"10.1016\/j.cub.2015.07.050","volume":"25","author":"C Pacelli","year":"2015","unstructured":"Pacelli C, Giguere N, Bourque MJ, Levesque M, Slack RS, Trudeau LE. Elevated mitochondrial bioenergetics and axonal arborization size are key contributors to the vulnerability of dopamine neurons. Curr Biol. 2015;25:2349\u201360.","journal-title":"Curr Biol"},{"key":"3667_CR27","doi-asserted-by":"publisher","DOI":"10.1186\/1749-8104-6-23","volume":"6","author":"MT Alves dos Santos","year":"2011","unstructured":"Alves dos Santos MT, Smidt MP. En1 and Wnt signaling in midbrain dopaminergic neuronal development. Neural Dev. 2011;6:23.","journal-title":"Neural Dev"},{"key":"3667_CR28","doi-asserted-by":"publisher","first-page":"12747","DOI":"10.1073\/pnas.1534900100","volume":"100","author":"G Castelo-Branco","year":"2003","unstructured":"Castelo-Branco G, Wagner J, Rodriguez FJ, Kele J, Sousa K, Rawal N, et al. Differential regulation of midbrain dopaminergic neuron development by Wnt-1, Wnt-3a, and Wnt-5a. Proc Natl Acad Sci USA. 2003;100:12747\u201352.","journal-title":"Proc Natl Acad Sci USA"},{"key":"3667_CR29","doi-asserted-by":"publisher","DOI":"10.1126\/science.adf1226","volume":"382","author":"E Braun","year":"2023","unstructured":"Braun E, Danan-Gotthold M, Borm LE, Lee KW, Vinsland E, Lonnerberg P, et al. Comprehensive cell atlas of the first-trimester developing human brain. Science. 2023;382:eadf1226.","journal-title":"Science"},{"key":"3667_CR30","doi-asserted-by":"publisher","first-page":"1018","DOI":"10.1016\/j.celrep.2014.07.016","volume":"8","author":"L Panman","year":"2014","unstructured":"Panman L, Papathanou M, Laguna A, Oosterveen T, Volakakis N, Acampora D, et al. Sox6 and Otx2 control the specification of substantia nigra and ventral tegmental area dopamine neurons. Cell Rep. 2014;8:1018\u201325.","journal-title":"Cell Rep"},{"key":"3667_CR31","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.89482","volume":"12","author":"B Yaghmaeian Salmani","year":"2024","unstructured":"Yaghmaeian Salmani B, Lahti L, Gillberg L, Jacobsen JK, Mantas I, Svenningsson P, et al. Transcriptomic atlas of midbrain dopamine neurons uncovers differential vulnerability in a Parkinsonism lesion model. Elife. 2024;12:RP89482.","journal-title":"Elife"},{"key":"3667_CR32","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2021.109975","volume":"37","author":"M Pereira Luppi","year":"2021","unstructured":"Pereira Luppi M, Azcorra M, Caronia-Brown G, Poulin JF, Gaertner Z, Gatica S, et al. Sox6 expression distinguishes dorsally and ventrally biased dopamine neurons in the substantia nigra with distinctive properties and embryonic origins. Cell Rep. 2021;37:109975.","journal-title":"Cell Rep"},{"key":"3667_CR33","doi-asserted-by":"publisher","first-page":"130","DOI":"10.1016\/j.brainres.2010.09.063","volume":"1367","author":"D Dardou","year":"2011","unstructured":"Dardou D, Dassesse D, Cuvelier L, Deprez T, De Ryck M, Schiffmann SN. Distribution of SV2C mRNA and protein expression in the mouse brain with a particular emphasis on the basal ganglia system. Brain Res. 2011;1367:130\u201345.","journal-title":"Brain Res"},{"key":"3667_CR34","doi-asserted-by":"publisher","first-page":"2181","DOI":"10.1242\/dev.129.9.2181","volume":"129","author":"E van den Akker","year":"2002","unstructured":"van den Akker E, Forlani S, Chawengsaksophak K, de Graaff W, Beck F, Meyer BI, et al. Cdx1 and Cdx2 have overlapping functions in anteroposterior patterning and posterior axis elongation. Development. 2002;129:2181\u201393.","journal-title":"Development"},{"key":"3667_CR35","doi-asserted-by":"publisher","first-page":"675","DOI":"10.1016\/S0896-6273(01)80027-1","volume":"23","author":"J Thaler","year":"1999","unstructured":"Thaler J, Harrison K, Sharma K, Lettieri K, Kehrl J, Pfaff SL. Active suppression of interneuron programs within developing motor neurons revealed by analysis of homeodomain factor HB9. Neuron. 1999;23:675\u201387.","journal-title":"Neuron"},{"key":"3667_CR36","doi-asserted-by":"crossref","unstructured":"Elder NH, Majd A, Bulger EA, Samuel RM, Zholudeva LV, McDevitt TC, et al. Distinct differentiation trajectories leave lasting impacts on gene regulation and function of V2a interneurons. bioRxiv [Preprint]. 2024 https:\/\/www.biorxiv.org\/content\/10.1101\/2024.12.03.626573v1.","DOI":"10.1101\/2024.12.03.626573"},{"key":"3667_CR37","doi-asserted-by":"publisher","first-page":"347","DOI":"10.1016\/j.mcn.2010.11.003","volume":"46","author":"JP Dugan","year":"2011","unstructured":"Dugan JP, Stratton A, Riley HP, Farmer WT, Mastick GS. Midbrain dopaminergic axons are guided longitudinally through the diencephalon by Slit\/Robo signals. Mol Cell Neurosci. 2011;46:347\u201356.","journal-title":"Mol Cell Neurosci"},{"key":"3667_CR38","doi-asserted-by":"publisher","first-page":"285","DOI":"10.1159\/000351023","volume":"35","author":"ME Cornide-Petronio","year":"2013","unstructured":"Cornide-Petronio ME, Barreiro-Iglesias A. Role of Slit and Robo proteins in the development of dopaminergic neurons. Dev Neurosci. 2013;35:285\u201392.","journal-title":"Dev Neurosci"},{"key":"3667_CR39","doi-asserted-by":"publisher","first-page":"128","DOI":"10.1038\/s41586-023-06913-9","volume":"626","author":"S Wang","year":"2024","unstructured":"Wang S, DeLeon C, Sun W, Quake SR, Roth BL, Sudhof TC. Alternative splicing of latrophilin-3 controls synapse formation. Nature. 2024;626:128\u201335.","journal-title":"Nature"},{"key":"3667_CR40","doi-asserted-by":"publisher","DOI":"10.1126\/science.aav7969","volume":"363","author":"R Sando","year":"2019","unstructured":"Sando R, Jiang X, Sudhof TC. Latrophilin GPCRs direct synapse specificity by coincident binding of FLRTs and teneurins. Science. 2019;363:eaav7969.","journal-title":"Science"},{"key":"3667_CR41","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.65717","volume":"10","author":"R Sando","year":"2021","unstructured":"Sando R, Sudhof TC. Latrophilin GPCR signaling mediates synapse formation. Elife. 2021;10:e65717.","journal-title":"Elife"},{"key":"3667_CR42","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1038\/s41422-023-00906-z","volume":"34","author":"Y Wang","year":"2024","unstructured":"Wang Y, Zhang P, Chao Y, Zhu Z, Yang C, Zhou Z, et al. Transport and inhibition mechanism for VMAT2-mediated synaptic vesicle loading of monoamines. Cell Res. 2024;34:47\u201357.","journal-title":"Cell Res"},{"key":"3667_CR43","doi-asserted-by":"publisher","first-page":"2591","DOI":"10.1002\/cne.23051","volume":"520","author":"S Reyes","year":"2012","unstructured":"Reyes S, Fu Y, Double K, Thompson L, Kirik D, Paxinos G, et al. GIRK2 expression in dopamine neurons of the substantia nigra and ventral tegmental area. J of Comparative Neurology. 2012;520:2591\u2013607.","journal-title":"J of Comparative Neurology"},{"key":"3667_CR44","doi-asserted-by":"publisher","first-page":"3032","DOI":"10.1172\/JCI72176","volume":"124","author":"G Liu","year":"2014","unstructured":"Liu G, Yu J, Ding J, Xie C, Sun L, Rudenko I, et al. Aldehyde dehydrogenase 1 defines and protects a nigrostriatal dopaminergic neuron subpopulation. J Clin Invest. 2014;124:3032\u201346.","journal-title":"J Clin Invest"},{"key":"3667_CR45","doi-asserted-by":"publisher","first-page":"165","DOI":"10.1038\/s41531-024-00777-0","volume":"10","author":"NL-G Del Rey","year":"2024","unstructured":"Del Rey NL-G, Hern\u00e1ndez-Pinedo N, Carrillo M, Del Cerro M, Esteban-Garc\u00eda N, Trigo-Damas I, et al. Calbindin and Girk2\/Aldh1a1 define resilient vs vulnerable dopaminergic neurons in a primate Parkinson\u2019s disease model. npj Parkinson\u2019s Disease. 2024;10:165.","journal-title":"npj Parkinson\u2019s Disease"},{"key":"3667_CR46","doi-asserted-by":"publisher","first-page":"788","DOI":"10.1111\/j.1750-3639.2012.00592.x","volume":"22","author":"SA Adam","year":"2012","unstructured":"Adam SA, Schnell O, Poschl J, Eigenbrod S, Kretzschmar HA, Tonn JC, et al. ALDH1A1 is a marker of astrocytic differentiation during brain development and correlates with better survival in glioblastoma patients. Brain Pathol. 2012;22:788\u201397.","journal-title":"Brain Pathol"},{"key":"3667_CR47","doi-asserted-by":"publisher","first-page":"57145","DOI":"10.1021\/acsomega.5c06482","volume":"10","author":"ACB Silva","year":"2025","unstructured":"Silva ACB, Esperanca MN, Badino AC, Bettega R. CFD modeling of shear-rate distribution in a bubble column bioreactor: influence of bubble diameter and lift force. ACS Omega. 2025;10:57145\u201356.","journal-title":"ACS Omega"},{"key":"3667_CR48","doi-asserted-by":"publisher","first-page":"7999","DOI":"10.1128\/MCB.01046-06","volume":"26","author":"G Liang","year":"2006","unstructured":"Liang G, Audas TE, Li Y, Cockram GP, Dean JD, Martyn AC, et al. Luman\/CREB3 induces transcription of the endoplasmic reticulum (ER) stress response protein Herp through an ER stress response element. Mol Cell Biol. 2006;26:7999\u20138010.","journal-title":"Mol Cell Biol"},{"key":"3667_CR49","doi-asserted-by":"publisher","first-page":"e39586","DOI":"10.1371\/journal.pone.0039586","volume":"7","author":"AP Ghosh","year":"2012","unstructured":"Ghosh AP, Klocke BJ, Ballestas ME, Roth KA. CHOP potentially co-operates with FOXO3a in neuronal cells to regulate PUMA and BIM expression in response to ER stress. PLoS One. 2012;7:e39586.","journal-title":"PLoS One"},{"key":"3667_CR50","doi-asserted-by":"publisher","first-page":"8270","DOI":"10.1039\/D2NR05487F","volume":"15","author":"S Jadavi","year":"2023","unstructured":"Jadavi S, Dante S, Civiero L, Sandre M, Bubacco L, Tosatto L, et al. Fluorescence labeling methods influence the aggregation process of \u03b1-syn in vitro differently. Nanoscale. 2023;15:8270\u20137.","journal-title":"Nanoscale"},{"key":"3667_CR51","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1007\/s00401-010-0676-z","volume":"120","author":"K Tanji","year":"2010","unstructured":"Tanji K, Mori F, Mimura J, Itoh K, Kakita A, Takahashi H, et al. Proteinase K-resistant \u03b1-synuclein is deposited in presynapses in human Lewy body disease and A53T \u03b1-synuclein transgenic mice. Acta Neuropathol. 2010;120:145\u201354.","journal-title":"Acta Neuropathol"},{"key":"3667_CR52","doi-asserted-by":"publisher","first-page":"1421","DOI":"10.1093\/brain\/122.8.1421","volume":"122","author":"P Damier","year":"1999","unstructured":"Damier P, Hirsch EC, Agid Y, Graybiel AM. The substantia nigra of the human brain. I. Nigrosomes and the nigral matrix, a compartmental organization based on calbindin D(28K) immunohistochemistry. Brain. 1999;122:1421\u201336.","journal-title":"Brain"},{"key":"3667_CR53","doi-asserted-by":"publisher","first-page":"3373","DOI":"10.1016\/j.celrep.2016.08.053","volume":"16","author":"KC Luk","year":"2016","unstructured":"Luk KC, Covell DJ, Kehm VM, Zhang B, Song IY, Byrne MD, et al. Molecular and biological compatibility with host alpha-synuclein influences fibril pathogenicity. Cell Rep. 2016;16:3373\u201387.","journal-title":"Cell Rep"},{"key":"3667_CR54","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1016\/j.jsb.2018.04.003","volume":"206","author":"S Hwang","year":"2019","unstructured":"Hwang S, Fricke P, Zinke M, Giller K, Wall JS, Riedel D, et al. Comparison of the 3D structures of mouse and human alpha-synuclein fibrils by solid-state NMR and STEM. J Struct Biol. 2019;206:43\u201348.","journal-title":"J Struct Biol"},{"key":"3667_CR55","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.adq3539","volume":"10","author":"A Sokratian","year":"2024","unstructured":"Sokratian A, Zhou Y, Tatli M, Burbidge KJ, Xu E, Viverette E, et al. Mouse alpha-synuclein fibrils are structurally and functionally distinct from human fibrils associated with Lewy body diseases. Sci Adv. 2024;10:eadq3539.","journal-title":"Sci Adv"},{"key":"3667_CR56","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-27464-5","volume":"12","author":"A Fiorenzano","year":"2021","unstructured":"Fiorenzano A, Sozzi E, Birtele M, Kajtez J, Giacomoni J, Nilsson F, et al. Single-cell transcriptomics captures features of human midbrain development and dopamine neuron diversity in brain organoids. Nat Commun. 2021;12:7302.","journal-title":"Nat Commun"},{"key":"3667_CR57","doi-asserted-by":"publisher","first-page":"2034","DOI":"10.1038\/s41592-023-02080-x","volume":"20","author":"D Reumann","year":"2023","unstructured":"Reumann D, Krauditsch C, Novatchkova M, Sozzi E, Wong SN, Zabolocki M, et al. In vitro modeling of the human dopaminergic system using spatially arranged ventral midbrain-striatum-cortex assembloids. Nat Methods. 2023;20:2034\u201347.","journal-title":"Nat Methods"},{"key":"3667_CR58","doi-asserted-by":"publisher","first-page":"248","DOI":"10.1016\/j.stem.2016.07.005","volume":"19","author":"J Jo","year":"2016","unstructured":"Jo J, Xiao Y, Sun AX, Cukuroglu E, Tran HD, Goke J, et al. Midbrain-like organoids from human pluripotent stem cells contain functional dopaminergic and neuromelanin-producing neurons. Cell Stem Cell. 2016;19:248\u201357.","journal-title":"Cell Stem Cell"},{"key":"3667_CR59","doi-asserted-by":"publisher","first-page":"547","DOI":"10.1038\/nature10648","volume":"480","author":"S Kriks","year":"2011","unstructured":"Kriks S, Shim JW, Piao J, Ganat YM, Wakeman DR, Xie Z, et al. Dopamine neurons derived from human ES cells efficiently engraft in animal models of Parkinson\u2019s disease. Nature. 2011;480:547\u201351.","journal-title":"Nature"},{"key":"3667_CR60","doi-asserted-by":"crossref","unstructured":"Kim TW, Piao J, Bocchi VD, Koo SY, Choi SJ, Chaudhry F, et al. Modulation of WNT and FGF18 enhances yield and subtype identity of hPSC-derived midbrain dopamine neurons. J Clin Invest. 2026;136:e190954.","DOI":"10.1172\/JCI190954"},{"key":"3667_CR61","doi-asserted-by":"publisher","first-page":"118","DOI":"10.1038\/s41531-024-00735-w","volume":"10","author":"T Balzano","year":"2024","unstructured":"Balzano T, Del Rey NL, Esteban-Garcia N, Reinares-Sebastian A, Pineda-Pardo JA, Trigo-Damas I, et al. Neurovascular and immune factors of vulnerability of substantia nigra dopaminergic neurons in non-human primates. NPJ Parkinsons Dis. 2024;10:118.","journal-title":"NPJ Parkinsons Dis"},{"key":"3667_CR62","doi-asserted-by":"publisher","first-page":"e0204269","DOI":"10.1371\/journal.pone.0204269","volume":"13","author":"A Al-Ani","year":"2018","unstructured":"Al-Ani A, Toms D, Kondro D, Thundathil J, Yu Y, Ungrin M. Oxygenation in cell culture: Critical parameters for reproducibility are routinely not reported. PLoS One. 2018;13:e0204269.","journal-title":"PLoS One"},{"key":"3667_CR63","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1152\/physrev.00041.2017","volume":"99","author":"TP Keeley","year":"2019","unstructured":"Keeley TP, Mann GE. Defining physiological normoxia for improved translation of cell physiology to animal models and humans. Physiol Rev. 2019;99:161\u2013234.","journal-title":"Physiol Rev"},{"key":"3667_CR64","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1016\/S0079-6123(06)60011-3","volume":"160","author":"JM Tepper","year":"2007","unstructured":"Tepper JM, Lee CR. GABAergic control of substantia nigra dopaminergic neurons. Prog Brain Res. 2007;160:189\u2013208.","journal-title":"Prog Brain Res"},{"key":"3667_CR65","doi-asserted-by":"publisher","first-page":"13","DOI":"10.3389\/fncom.2013.00013","volume":"7","author":"EK Pissadaki","year":"2013","unstructured":"Pissadaki EK, Bolam JP. The energy cost of action potential propagation in dopamine neurons: clues to susceptibility in Parkinson\u2019s disease. Front Comput Neurosci. 2013;7:13.","journal-title":"Front Comput Neurosci"},{"key":"3667_CR66","doi-asserted-by":"publisher","first-page":"762","DOI":"10.1016\/j.neuron.2012.08.019","volume":"75","author":"JJ Harris","year":"2012","unstructured":"Harris JJ, Jolivet R, Attwell D. Synaptic energy use and supply. Neuron. 2012;75:762\u201377.","journal-title":"Neuron"},{"key":"3667_CR67","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1038\/nrn.2016.178","volume":"18","author":"DJ Surmeier","year":"2017","unstructured":"Surmeier DJ, Obeso JA, Halliday GM. Selective neuronal vulnerability in Parkinson disease. Nat Rev Neurosci. 2017;18:101\u201313.","journal-title":"Nat Rev Neurosci"},{"key":"3667_CR68","doi-asserted-by":"publisher","first-page":"1663","DOI":"10.1126\/science.1195227","volume":"329","author":"J Burre","year":"2010","unstructured":"Burre J, Sharma M, Tsetsenis T, Buchman V, Etherton MR, Sudhof TC. Alpha-synuclein promotes SNARE-complex assembly in vivo and in vitro. Science. 2010;329:1663\u20137.","journal-title":"Science"},{"key":"3667_CR69","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2021.626128","volume":"15","author":"NZ Gcwensa","year":"2021","unstructured":"Gcwensa NZ, Russell DL, Cowell RM, Volpicelli-Daley LA. Molecular mechanisms underlying synaptic and axon degeneration in Parkinson\u2019s disease. Front Cell Neurosci. 2021;15:626128.","journal-title":"Front Cell Neurosci"},{"key":"3667_CR70","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1038\/s41531-023-00444-w","volume":"9","author":"N Ramalingam","year":"2023","unstructured":"Ramalingam N, Jin SX, Moors TE, Fonseca-Ornelas L, Shimanaka K, Lei S, et al. Dynamic physiological alpha-synuclein S129 phosphorylation is driven by neuronal activity. NPJ Parkinsons Dis. 2023;9:4.","journal-title":"NPJ Parkinsons Dis"},{"key":"3667_CR71","doi-asserted-by":"publisher","first-page":"4006","DOI":"10.1016\/j.neuron.2023.11.020","volume":"111","author":"LA Parra-Rivas","year":"2023","unstructured":"Parra-Rivas LA, Madhivanan K, Aulston BD, Wang L, Prakashchand DD, Boyer NP, et al. Serine-129 phosphorylation of alpha-synuclein is an activity-dependent trigger for physiologic protein-protein interactions and synaptic function. Neuron. 2023;111:4006\u201323.e4010.","journal-title":"Neuron"},{"key":"3667_CR72","first-page":"1","volume":"10","author":"M Madadi Asl","year":"2019","unstructured":"Madadi Asl M, Vahabie AH, Valizadeh A. Dopaminergic modulation of synaptic plasticity, its role in neuropsychiatric disorders, and its computational modeling. Basic Clin Neurosci. 2019;10:1\u201312.","journal-title":"Basic Clin Neurosci"},{"key":"3667_CR73","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1016\/S1474-4422(21)00330-6","volume":"21","author":"D Weintraub","year":"2022","unstructured":"Weintraub D, Aarsland D, Chaudhuri KR, Dobkin RD, Leentjens AF, Rodriguez-Violante M, et al. The neuropsychiatry of Parkinson\u2019s disease: advances and challenges. Lancet Neurol. 2022;21:89\u2013102.","journal-title":"Lancet Neurol"},{"key":"3667_CR74","doi-asserted-by":"publisher","first-page":"709","DOI":"10.3390\/antiox13060709","volume":"13","author":"NS Rawani","year":"2024","unstructured":"Rawani NS, Chan AW, Dursun SM, Baker GB. The underlying neurobiological mechanisms of psychosis: focus on neurotransmission dysregulation, neuroinflammation, oxidative stress, and mitochondrial dysfunction. Antioxidants (Basel). 2024;13:709.","journal-title":"Antioxidants (Basel)"},{"key":"3667_CR75","doi-asserted-by":"publisher","first-page":"5733","DOI":"10.1038\/s41380-020-0807-4","volume":"26","author":"MJ P\u00e9rez","year":"2021","unstructured":"P\u00e9rez MJ, Ivanyuk D, Panagiotakopoulou V, Di Napoli G, Kalb S, Brunetti D, et al. Loss of function of the mitochondrial peptidase PITRM1 induces proteotoxic stress and Alzheimer\u2019s disease-like pathology in human cerebral organoids. Molecular Psychiatry. 2021;26:5733\u201350.","journal-title":"Molecular Psychiatry"},{"key":"3667_CR76","doi-asserted-by":"publisher","first-page":"2976","DOI":"10.1016\/j.celrep.2018.05.009","volume":"23","author":"DC Sch\u00f6ndorf","year":"2018","unstructured":"Sch\u00f6ndorf DC, Ivanyuk D, Baden P, Sanchez-Martinez A, De Cicco S, Yu C, et al. The NAD+ precursor nicotinamide riboside rescues mitochondrial defects and neuronal loss in iPSC and fly models of Parkinson\u2019s disease. Cell Reports. 2018;23:2976\u201388.","journal-title":"Cell Reports"},{"key":"3667_CR77","doi-asserted-by":"publisher","first-page":"411","DOI":"10.1038\/nbt.4096","volume":"36","author":"A Butler","year":"2018","unstructured":"Butler A, Hoffman P, Smibert P, Papalexi E, Satija R. Integrating single-cell transcriptomic data across different conditions, technologies, and species. Nat Biotechnol. 2018;36:411\u201320.","journal-title":"Nat Biotechnol"},{"key":"3667_CR78","doi-asserted-by":"publisher","first-page":"1888","DOI":"10.1016\/j.cell.2019.05.031","volume":"177","author":"T Stuart","year":"2019","unstructured":"Stuart T, Butler A, Hoffman P, Hafemeister C, Papalexi E, Mauck WM 3rd, et al. Comprehensive integration of single-cell data. Cell. 2019;177:1888\u2013902.e1821.","journal-title":"Cell"},{"key":"3667_CR79","doi-asserted-by":"publisher","DOI":"10.1186\/s12864-018-4772-0","volume":"19","author":"K Street","year":"2018","unstructured":"Street K, Risso D, Fletcher RB, Das D, Ngai J, Yosef N, et al. Slingshot: cell lineage and pseudotime inference for single-cell transcriptomics. BMC Genomics. 2018;19:477.","journal-title":"BMC Genomics"},{"key":"3667_CR80","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-14766-3","volume":"11","author":"K Van den Berge","year":"2020","unstructured":"Van den Berge K, Roux de Bezieux H, Street K, Saelens W, Cannoodt R, Saeys Y, et al. Trajectory-based differential expression analysis for single-cell sequencing data. Nat Commun. 2020;11:1201.","journal-title":"Nat Commun"},{"key":"3667_CR81","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1038\/s41587-021-01033-z","volume":"40","author":"E Dann","year":"2022","unstructured":"Dann E, Henderson NC, Teichmann SA, Morgan MD, Marioni JC. Differential abundance testing on single-cell data using k-nearest neighbor graphs. Nat Biotechnol. 2022;40:245\u201353.","journal-title":"Nat Biotechnol"},{"key":"3667_CR82","doi-asserted-by":"publisher","first-page":"171","DOI":"10.1007\/978-1-0716-1534-8_10","volume":"2328","author":"N Kumar","year":"2021","unstructured":"Kumar N, Mishra B, Athar M, Mukhtar S. Inference of gene regulatory network from single-cell transcriptomic data using pySCENIC. Methods Mol Biol. 2021;2328:171\u201382.","journal-title":"Methods Mol Biol"},{"key":"3667_CR83","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-21246-9","volume":"12","author":"S Jin","year":"2021","unstructured":"Jin S, Guerrero-Juarez CF, Zhang L, Chang I, Ramos R, Kuan CH, et al. Inference and analysis of cell-cell communication using CellChat. Nat Commun. 2021;12:1088.","journal-title":"Nat Commun"},{"key":"3667_CR84","doi-asserted-by":"publisher","unstructured":"Singh V, Castellana-Cruz M, Cremades N, Volpicelli-Daley L Generation and Sonication of \u03b1-synuclein Fibrils v1. 2020. Protocols.io https:\/\/doi.org\/10.17504\/protocols.io.bhhrj356.","DOI":"10.17504\/protocols.io.bhhrj356"},{"key":"3667_CR85","doi-asserted-by":"publisher","first-page":"303","DOI":"10.3233\/JPD-171248","volume":"8","author":"NK Polinski","year":"2018","unstructured":"Polinski NK, Volpicelli-Daley LA, Sortwell CE, Luk KC, Cremades N, Gottler LM, et al. Best practices for generating and using alpha-synuclein pre-formed fibrils to model Parkinson\u2019s disease in rodents. Journal of Parkinson\u2019s Disease. 2018;8:303\u201322.","journal-title":"Journal of Parkinson\u2019s Disease"}],"container-title":["Molecular Psychiatry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41380-026-03667-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41380-026-03667-4","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41380-026-03667-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T09:03:41Z","timestamp":1789117421000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41380-026-03667-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,17]]},"references-count":85,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2026,10]]}},"alternative-id":["3667"],"URL":"https:\/\/doi.org\/10.1038\/s41380-026-03667-4","relation":{},"ISSN":["1359-4184","1476-5578"],"issn-type":[{"value":"1359-4184","type":"print"},{"value":"1476-5578","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,17]]},"assertion":[{"value":"21 October 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 April 2026","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"22 May 2026","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"17 June 2026","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Ethics"}}]}}