271722 20260310111152.0 pmc:PMC11384962 pmc 10.1016/j.xcrm.2024.101659 doi pmid:39067446 pmid altmetric:165709696 altmetric DZNE-2024-01074 English 610 Grass, Tobias P:(DE-2719)9000564 0 First author dzne Isogenic patient-derived organoids reveal early neurodevelopmental defects in spinal muscular atrophy initiation. Maryland Heights, MO 2024 Elsevier article DRIVER Output Types/Journal article DataCite Journal Article journal journal PUB:(DE-HGF)16 1733226931_30592 PUB:(DE-HGF) ARTICLE BibTeX JOURNAL_ARTICLE ORCID Journal Article 0 EndNote Whether neurodevelopmental defects underlie postnatal neuronal death in neurodegeneration is an intriguing hypothesis only recently explored. Here, we focus on spinal muscular atrophy (SMA), a neuromuscular disorder caused by reduced survival of motor neuron (SMN) protein levels leading to spinal motor neuron (MN) loss and muscle wasting. Using the first isogenic patient-derived induced pluripotent stem cell (iPSC) model and a spinal cord organoid (SCO) system, we show that SMA SCOs exhibit abnormal morphological development, reduced expression of early neural progenitor markers, and accelerated expression of MN progenitor and MN markers. Longitudinal single-cell RNA sequencing reveals marked defects in neural stem cell specification and fewer MNs, favoring mesodermal progenitors and muscle cells, a bias also seen in early SMA mouse embryos. Surprisingly, SMN2-to-SMN1 conversion does not fully reverse these developmental abnormalities. These suggest that early neurodevelopmental defects may underlie later MN degeneration, indicating that postnatal SMN-increasing interventions might not completely amend SMA pathology in all patients. 352 - Disease Mechanisms (POF4-352) G:(DE-HGF)POF4-352 POF4-352 POF IV 0 351 - Brain Function (POF4-351) G:(DE-HGF)POF4-351 POF4-351 POF IV 1 354 - Disease Prevention and Healthy Aging (POF4-354) G:(DE-HGF)POF4-354 POF4-354 POF IV 2 Dataset connected to CrossRef, PubMed, , Journals: pub.dzne.de isogenic SMA model Other neurodevelopmental defects Other neuromesodermal progenitors Other organoids Other spinal cord Other Survival of Motor Neuron 1 Protein NLM Chemicals Survival of Motor Neuron 2 Protein NLM Chemicals SMN2 protein, human NLM Chemicals SMN1 protein, human NLM Chemicals Organoids: pathology MeSH Organoids: metabolism MeSH Humans MeSH Muscular Atrophy, Spinal: pathology MeSH Muscular Atrophy, Spinal: genetics MeSH Muscular Atrophy, Spinal: metabolism MeSH Induced Pluripotent Stem Cells: metabolism MeSH Induced Pluripotent Stem Cells: pathology MeSH Motor Neurons: pathology MeSH Motor Neurons: metabolism MeSH Survival of Motor Neuron 1 Protein: genetics MeSH Survival of Motor Neuron 1 Protein: metabolism MeSH Survival of Motor Neuron 2 Protein: genetics MeSH Survival of Motor Neuron 2 Protein: metabolism MeSH Animals MeSH Mice MeSH Spinal Cord: pathology MeSH Spinal Cord: metabolism MeSH Neural Stem Cells: metabolism MeSH Neural Stem Cells: pathology MeSH EXP:(DE-2719)PRECISE-20190321 EXP:(DE-2719)PRECISE-20190321 Platform for Single Cell Genomics and Epigenomics at DZNE University of Bonn 0 Dokuzluoglu, Zeynep P:(DE-2719)9002364 1 dzne Buchner, Felix P:(DE-2719)9001904 2 dzne Rosignol, Ines P:(DE-2719)9000727 3 dzne Thomas, Joshua P:(DE-2719)9001330 4 dzne Caldarelli, Antonio P:(DE-2719)9002525 5 dzne Dalinskaya, Anna P:(DE-2719)9002286 6 dzne Becker, Jutta 7 Rost, Fabian 8 Marass, Michele 9 Wirth, Brunhilde 10 Beyer, Marc P:(DE-2719)2812219 11 dzne Bonaguro, Lorenzo P:(DE-2719)9001512 12 dzne Rodriguez-Muela, Natalia P:(DE-2719)9000726 13 Last author dzne 10.1016/j.xcrm.2024.101659 Vol. 5, no. 8, p. 101659 - PERI:(DE-600)3019420-9 8 101659 Cell reports / Medicine 5 2024 2666-3791 http://pub.dzne.de/record/271722/files/DZNE-2024-01074%20SUP.zip http://pub.dzne.de/record/271722/files/DZNE-2024-01074.pdf OpenAccess http://pub.dzne.de/record/271722/files/DZNE-2024-01074.pdf?subformat=pdfa pdfa OpenAccess #637 4148 APC 2026-03-09 DEAL 2024-12-11 oai:pub.dzne.de:271722 openaire open_access OpenAPC driver VDB openCost dnbdelivery Deutsches Zentrum für Neurodegenerative Erkrankungen I:(DE-588)1065079516 DZNE 0 P:(DE-2719)9000564 Deutsches Zentrum für Neurodegenerative Erkrankungen I:(DE-588)1065079516 DZNE 1 P:(DE-2719)9002364 Deutsches Zentrum für Neurodegenerative Erkrankungen I:(DE-588)1065079516 DZNE 2 P:(DE-2719)9001904 Deutsches Zentrum für Neurodegenerative Erkrankungen I:(DE-588)1065079516 DZNE 3 P:(DE-2719)9000727 Deutsches Zentrum für Neurodegenerative Erkrankungen I:(DE-588)1065079516 DZNE 4 P:(DE-2719)9001330 Deutsches Zentrum für Neurodegenerative Erkrankungen I:(DE-588)1065079516 DZNE 5 P:(DE-2719)9002525 Deutsches Zentrum für Neurodegenerative Erkrankungen I:(DE-588)1065079516 DZNE 6 P:(DE-2719)9002286 Deutsches Zentrum für Neurodegenerative Erkrankungen I:(DE-588)1065079516 DZNE 11 P:(DE-2719)2812219 Deutsches Zentrum für Neurodegenerative Erkrankungen I:(DE-588)1065079516 DZNE 12 P:(DE-2719)9001512 Deutsches Zentrum für Neurodegenerative Erkrankungen I:(DE-588)1065079516 DZNE 13 P:(DE-2719)9000726 DE-HGF Gesundheit Neurodegenerative Diseases G:(DE-HGF)POF4-350 G:(DE-HGF)POF4-352 G:(DE-HGF)POF4 G:(DE-HGF)POF4-300 G:(DE-HGF)POF Disease Mechanisms 0 DE-HGF Gesundheit Neurodegenerative Diseases G:(DE-HGF)POF4-350 G:(DE-HGF)POF4-351 G:(DE-HGF)POF4 G:(DE-HGF)POF4-300 G:(DE-HGF)POF Brain Function 1 DE-HGF Gesundheit Neurodegenerative Diseases G:(DE-HGF)POF4-350 G:(DE-HGF)POF4-354 G:(DE-HGF)POF4 G:(DE-HGF)POF4-300 G:(DE-HGF)POF Disease Prevention and Healthy Aging 2 2024 DBCoverage StatID:(DE-HGF)0200 StatID SCOPUS 2023-08-22 DBCoverage StatID:(DE-HGF)0160 StatID Essential Science Indicators 2023-08-22 DBCoverage StatID:(DE-HGF)1050 StatID BIOSIS Previews 2023-08-22 DBCoverage StatID:(DE-HGF)1190 StatID Biological Abstracts 2023-08-22 Creative Commons Attribution CC BY 4.0 LIC:(DE-HGF)CCBY4 HGFVOC JCR StatID:(DE-HGF)0100 StatID CELL REP MED : 2022 2023-08-22 DBCoverage StatID:(DE-HGF)1030 StatID Current Contents - 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