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000271722 1001_ $$0P:(DE-2719)9000564$$aGrass, Tobias$$b0$$eFirst author$$udzne
000271722 245__ $$aIsogenic patient-derived organoids reveal early neurodevelopmental defects in spinal muscular atrophy initiation.
000271722 260__ $$aMaryland Heights, MO$$bElsevier$$c2024
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000271722 520__ $$aWhether 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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000271722 650_7 $$2Other$$aisogenic SMA model
000271722 650_7 $$2Other$$aneurodevelopmental defects
000271722 650_7 $$2Other$$aneuromesodermal progenitors
000271722 650_7 $$2Other$$aorganoids
000271722 650_7 $$2Other$$aspinal cord
000271722 650_7 $$2NLM Chemicals$$aSurvival of Motor Neuron 1 Protein
000271722 650_7 $$2NLM Chemicals$$aSurvival of Motor Neuron 2 Protein
000271722 650_7 $$2NLM Chemicals$$aSMN2 protein, human
000271722 650_7 $$2NLM Chemicals$$aSMN1 protein, human
000271722 650_2 $$2MeSH$$aOrganoids: pathology
000271722 650_2 $$2MeSH$$aOrganoids: metabolism
000271722 650_2 $$2MeSH$$aHumans
000271722 650_2 $$2MeSH$$aMuscular Atrophy, Spinal: pathology
000271722 650_2 $$2MeSH$$aMuscular Atrophy, Spinal: genetics
000271722 650_2 $$2MeSH$$aMuscular Atrophy, Spinal: metabolism
000271722 650_2 $$2MeSH$$aInduced Pluripotent Stem Cells: metabolism
000271722 650_2 $$2MeSH$$aInduced Pluripotent Stem Cells: pathology
000271722 650_2 $$2MeSH$$aMotor Neurons: pathology
000271722 650_2 $$2MeSH$$aMotor Neurons: metabolism
000271722 650_2 $$2MeSH$$aSurvival of Motor Neuron 1 Protein: genetics
000271722 650_2 $$2MeSH$$aSurvival of Motor Neuron 1 Protein: metabolism
000271722 650_2 $$2MeSH$$aSurvival of Motor Neuron 2 Protein: genetics
000271722 650_2 $$2MeSH$$aSurvival of Motor Neuron 2 Protein: metabolism
000271722 650_2 $$2MeSH$$aAnimals
000271722 650_2 $$2MeSH$$aMice
000271722 650_2 $$2MeSH$$aSpinal Cord: pathology
000271722 650_2 $$2MeSH$$aSpinal Cord: metabolism
000271722 650_2 $$2MeSH$$aNeural Stem Cells: metabolism
000271722 650_2 $$2MeSH$$aNeural Stem Cells: pathology
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000271722 7001_ $$0P:(DE-2719)9002364$$aDokuzluoglu, Zeynep$$b1$$udzne
000271722 7001_ $$0P:(DE-2719)9001904$$aBuchner, Felix$$b2$$udzne
000271722 7001_ $$0P:(DE-2719)9000727$$aRosignol, Ines$$b3$$udzne
000271722 7001_ $$0P:(DE-2719)9001330$$aThomas, Joshua$$b4$$udzne
000271722 7001_ $$0P:(DE-2719)9002525$$aCaldarelli, Antonio$$b5$$udzne
000271722 7001_ $$0P:(DE-2719)9002286$$aDalinskaya, Anna$$b6$$udzne
000271722 7001_ $$aBecker, Jutta$$b7
000271722 7001_ $$aRost, Fabian$$b8
000271722 7001_ $$aMarass, Michele$$b9
000271722 7001_ $$aWirth, Brunhilde$$b10
000271722 7001_ $$0P:(DE-2719)2812219$$aBeyer, Marc$$b11$$udzne
000271722 7001_ $$0P:(DE-2719)9001512$$aBonaguro, Lorenzo$$b12$$udzne
000271722 7001_ $$0P:(DE-2719)9000726$$aRodriguez-Muela, Natalia$$b13$$eLast author$$udzne
000271722 773__ $$0PERI:(DE-600)3019420-9$$a10.1016/j.xcrm.2024.101659$$gVol. 5, no. 8, p. 101659 -$$n8$$p101659$$tCell reports / Medicine$$v5$$x2666-3791$$y2024
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