{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:21:09Z","timestamp":1790814069095,"version":"4.1.0"},"reference-count":52,"publisher":"National Academy of Sciences","issue":"22","license":[{"start":{"date-parts":[[2024,5,21]],"date-time":"2024-05-21T00:00:00Z","timestamp":1716249600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2024,5,28]]},"abstract":"<jats:p>The striato-nigral (Str-SN) circuit is composed of medium spiny neuronal projections that are mainly sent from the striatum to the midbrain substantial nigra (SN), which is essential for regulating motor behaviors. Dysfunction of the Str-SN circuitry may cause a series of motor disabilities that are associated with neurodegenerative disorders, such as Huntington\u2019s disease (HD). Although the etiology of HD is known as abnormally expanded CAG repeats of the huntingtin gene, treatment of HD remains tremendously challenging. One possible reason is the lack of effective HD model that resembles Str-SN circuitry deficits for pharmacological studies. Here, we first differentiated striatum-like organoids from human pluripotent stem cells (hPSCs), containing functional medium spiny neurons (MSNs). We then generated 3D Str-SN assembloids by assembling striatum-like organoids with midbrain SN-like organoids. With AAV-hSYN-GFP-mediated viral tracing, extensive MSN projections from the striatum to the SN are established, which formed synaptic connection with GABAergic neurons in SN organoids and showed the optically evoked inhibitory postsynaptic currents and electronic field potentials by labeling the striatum-like organoids with optogenetic virus. Furthermore, these Str-SN assembloids exhibited enhanced calcium activity compared to that of individual striatal organoids. Importantly, we further demonstrated the reciprocal projection defects in HD iPSC-derived assembloids, which could be ameliorated by treatment of brain-derived neurotrophic factor. Taken together, these findings suggest that Str-SN assembloids could be used for identifying MSN projection defects and could be applied as potential drug test platforms for HD.<\/jats:p>","DOI":"10.1073\/pnas.2316176121","type":"journal-article","created":{"date-parts":[[2024,5,21]],"date-time":"2024-05-21T13:47:30Z","timestamp":1716299250000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":41,"title":["Construction of human 3D striato-nigral assembloids to recapitulate medium spiny neuronal projection defects in Huntington\u2019s disease"],"prefix":"10.1073","volume":"121","author":[{"given":"Shanshan","family":"Wu","sequence":"first","affiliation":[{"name":"State Key Laboratory of Reproductive Medicine and Offspring Health, Nanjing Medical University, Nanjing 211166, China"},{"name":"Institute for Stem Cell and Neural Regeneration, School of Pharmacy, Nanjing Medical University, Nanjing 211166, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Hong","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Reproductive Medicine and Offspring Health, Nanjing Medical University, Nanjing 211166, China"},{"name":"Institute for Stem Cell and Neural Regeneration, School of Pharmacy, Nanjing Medical University, Nanjing 211166, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chu","family":"Chu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Reproductive Medicine and Offspring Health, Nanjing Medical University, Nanjing 211166, China"},{"name":"Institute for Stem Cell and Neural Regeneration, School of Pharmacy, Nanjing Medical University, Nanjing 211166, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yixia","family":"Gan","sequence":"additional","affiliation":[{"name":"Key Laboratory of Adolescent Health Assessment and Exercise Intervention of Ministry of Education, East China Normal University, Shanghai 200241, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinrui","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Reproductive Medicine and Offspring Health, Nanjing Medical University, Nanjing 211166, China"},{"name":"Institute for Stem Cell and Neural Regeneration, School of Pharmacy, Nanjing Medical University, Nanjing 211166, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengdan","family":"Tao","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Reproductive Medicine and Offspring Health, Nanjing Medical University, Nanjing 211166, China"},{"name":"School of Biological Science and Medical Engineering Southeast University, Sipailou, Nanjing 210096, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Da","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Reproductive Medicine and Offspring Health, Nanjing Medical University, Nanjing 211166, China"},{"name":"Institute for Stem Cell and Neural Regeneration, School of Pharmacy, Nanjing Medical University, Nanjing 211166, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Hu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Reproductive Medicine and Offspring Health, Nanjing Medical University, Nanjing 211166, China"},{"name":"Institute for Stem Cell and Neural Regeneration, School of Pharmacy, Nanjing Medical University, Nanjing 211166, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhilong","family":"Zheng","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Reproductive Medicine and Offspring Health, Nanjing Medical University, Nanjing 211166, China"},{"name":"Department of Neurobiology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing 211166, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Zhu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Reproductive Medicine and Offspring Health, Nanjing Medical University, Nanjing 211166, China"},{"name":"Institute for Stem Cell and Neural Regeneration, School of Pharmacy, Nanjing Medical University, Nanjing 211166, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao","family":"Han","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Reproductive Medicine and Offspring Health, Nanjing Medical University, Nanjing 211166, China"},{"name":"Institute for Stem Cell and Neural Regeneration, School of Pharmacy, Nanjing Medical University, Nanjing 211166, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6292-4108","authenticated-orcid":false,"given":"Wanying","family":"Zhu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Reproductive Medicine and Offspring Health, Nanjing Medical University, Nanjing 211166, China"},{"name":"Institute for Stem Cell and Neural Regeneration, School of Pharmacy, Nanjing Medical University, Nanjing 211166, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Xu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Reproductive Medicine and Offspring Health, Nanjing Medical University, Nanjing 211166, China"},{"name":"Institute for Stem Cell and Neural Regeneration, School of Pharmacy, Nanjing Medical University, Nanjing 211166, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0183-4747","authenticated-orcid":false,"given":"Yi","family":"Dong","sequence":"additional","affiliation":[{"name":"Key Laboratory of Adolescent Health Assessment and Exercise Intervention of Ministry of Education, East China Normal University, Shanghai 200241, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Liu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Reproductive Medicine and Offspring Health, Nanjing Medical University, Nanjing 211166, China"},{"name":"Institute for Stem Cell and Neural Regeneration, School of Pharmacy, Nanjing Medical University, Nanjing 211166, China"},{"name":"School of Biological Science and Medical Engineering Southeast University, Sipailou, Nanjing 210096, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0216-0310","authenticated-orcid":false,"given":"Xing","family":"Guo","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Reproductive Medicine and Offspring Health, Nanjing Medical University, Nanjing 211166, China"},{"name":"Department of Neurobiology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing 211166, China"},{"name":"Co-innovation Center of Neuroregeneration, Nantong University, Jiangsu 226001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2024,5,21]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2291-21.2022"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.2147780"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2008.11.005"},{"key":"e_1_3_4_4_2","first-page":"51","article-title":"The basal ganglia and disorders of movement: Pathophysiological mechanisms","volume":"17","author":"Obeso J. A.","year":"2002","unstructured":"J. A. Obeso, M. C. Rodr\u00edguez-Oroz, M. Rodr\u00edguez, J. Arbizu, J. M. Gim\u00e9nez-Amaya, The basal ganglia and disorders of movement: Pathophysiological mechanisms. News Physiol. Sci. 17, 51\u201355 (2002).","journal-title":"News Physiol. 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Wu Construction of human 3D striato nigral circuitoids to recapitulate medium spiny neuronal projection defects in Huntington disease. Gene Expression Omnibus. https:\/\/www.ncbi.nlm.nih.gov\/geo\/query\/acc.cgi?acc=GSE251684. Deposited 20 December 2023.","DOI":"10.1073\/pnas.2316176121"},{"key":"e_1_3_4_52_2","doi-asserted-by":"crossref","unstructured":"C. Liu Mitochondrial HSF1 triggers mitochondrial dysfunction and neurodegeneration in Huntington\u2019s disease. Gene Expression Omnibus. https:\/\/www.ncbi.nlm.nih.gov\/geo\/query\/acc.cgi?acc=GSE198927. Deposited 18 May 2022.","DOI":"10.15252\/emmm.202215851"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2316176121","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,11,19]],"date-time":"2024-11-19T11:00:00Z","timestamp":1732014000000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2316176121"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,5,21]]},"references-count":52,"journal-issue":{"issue":"22","published-print":{"date-parts":[[2024,5,28]]}},"alternative-id":["10.1073\/pnas.2316176121"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2316176121","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,5,21]]},"assertion":[{"value":"2023-09-26","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-04-22","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-05-21","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2316176121"}}