Home > Publications Database > Isogenic patient-derived organoids reveal early neurodevelopmental defects in spinal muscular atrophy initiation. > print

001     271722
005     20250127091647.0
024 7 _ |a pmc:PMC11384962
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024 7 _ |a 10.1016/j.xcrm.2024.101659
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037 _ _ |a DZNE-2024-01074
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082 _ _ |a 610
100 1 _ |a Grass, Tobias
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245 _ _ |a Isogenic patient-derived organoids reveal early neurodevelopmental defects in spinal muscular atrophy initiation.
260 _ _ |a Maryland Heights, MO
|c 2024
|b Elsevier
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520 _ _ |a 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.
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650 _ 7 |a isogenic SMA model
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650 _ 7 |a neurodevelopmental defects
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650 _ 7 |a neuromesodermal progenitors
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650 _ 7 |a organoids
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650 _ 7 |a spinal cord
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650 _ 7 |a Survival of Motor Neuron 1 Protein
|2 NLM Chemicals
650 _ 7 |a Survival of Motor Neuron 2 Protein
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650 _ 7 |a SMN2 protein, human
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650 _ 7 |a SMN1 protein, human
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650 _ 2 |a Organoids: pathology
|2 MeSH
650 _ 2 |a Organoids: metabolism
|2 MeSH
650 _ 2 |a Humans
|2 MeSH
650 _ 2 |a Muscular Atrophy, Spinal: pathology
|2 MeSH
650 _ 2 |a Muscular Atrophy, Spinal: genetics
|2 MeSH
650 _ 2 |a Muscular Atrophy, Spinal: metabolism
|2 MeSH
650 _ 2 |a Induced Pluripotent Stem Cells: metabolism
|2 MeSH
650 _ 2 |a Induced Pluripotent Stem Cells: pathology
|2 MeSH
650 _ 2 |a Motor Neurons: pathology
|2 MeSH
650 _ 2 |a Motor Neurons: metabolism
|2 MeSH
650 _ 2 |a Survival of Motor Neuron 1 Protein: genetics
|2 MeSH
650 _ 2 |a Survival of Motor Neuron 1 Protein: metabolism
|2 MeSH
650 _ 2 |a Survival of Motor Neuron 2 Protein: genetics
|2 MeSH
650 _ 2 |a Survival of Motor Neuron 2 Protein: metabolism
|2 MeSH
650 _ 2 |a Animals
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650 _ 2 |a Mice
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650 _ 2 |a Spinal Cord: pathology
|2 MeSH
650 _ 2 |a Spinal Cord: metabolism
|2 MeSH
650 _ 2 |a Neural Stem Cells: metabolism
|2 MeSH
650 _ 2 |a Neural Stem Cells: pathology
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700 1 _ |a Dokuzluoglu, Zeynep
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700 1 _ |a Buchner, Felix
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700 1 _ |a Rosignol, Ines
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700 1 _ |a Thomas, Joshua
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700 1 _ |a Caldarelli, Antonio
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700 1 _ |a Dalinskaya, Anna
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700 1 _ |a Becker, Jutta
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700 1 _ |a Rost, Fabian
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700 1 _ |a Marass, Michele
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700 1 _ |a Wirth, Brunhilde
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700 1 _ |a Beyer, Marc
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700 1 _ |a Bonaguro, Lorenzo
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700 1 _ |a Rodriguez-Muela, Natalia
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773 _ _ |a 10.1016/j.xcrm.2024.101659
|g Vol. 5, no. 8, p. 101659 -
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