TY  - JOUR
AU  - Grass, Tobias
AU  - Dokuzluoglu, Zeynep
AU  - Buchner, Felix
AU  - Rosignol, Ines
AU  - Thomas, Joshua
AU  - Caldarelli, Antonio
AU  - Dalinskaya, Anna
AU  - Becker, Jutta
AU  - Rost, Fabian
AU  - Marass, Michele
AU  - Wirth, Brunhilde
AU  - Beyer, Marc
AU  - Bonaguro, Lorenzo
AU  - Rodriguez-Muela, Natalia
TI  - Isogenic patient-derived organoids reveal early neurodevelopmental defects in spinal muscular atrophy initiation.
JO  - Cell reports / Medicine
VL  - 5
IS  - 8
SN  - 2666-3791
CY  - Maryland Heights, MO
PB  - Elsevier
M1  - DZNE-2024-01074
SP  - 101659
PY  - 2024
AB  - 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.
KW  - Organoids: pathology
KW  - Organoids: metabolism
KW  - Humans
KW  - Muscular Atrophy, Spinal: pathology
KW  - Muscular Atrophy, Spinal: genetics
KW  - Muscular Atrophy, Spinal: metabolism
KW  - Induced Pluripotent Stem Cells: metabolism
KW  - Induced Pluripotent Stem Cells: pathology
KW  - Motor Neurons: pathology
KW  - Motor Neurons: metabolism
KW  - Survival of Motor Neuron 1 Protein: genetics
KW  - Survival of Motor Neuron 1 Protein: metabolism
KW  - Survival of Motor Neuron 2 Protein: genetics
KW  - Survival of Motor Neuron 2 Protein: metabolism
KW  - Animals
KW  - Mice
KW  - Spinal Cord: pathology
KW  - Spinal Cord: metabolism
KW  - Neural Stem Cells: metabolism
KW  - Neural Stem Cells: pathology
KW  - isogenic SMA model (Other)
KW  - neurodevelopmental defects (Other)
KW  - neuromesodermal progenitors (Other)
KW  - organoids (Other)
KW  - spinal cord (Other)
KW  - Survival of Motor Neuron 1 Protein (NLM Chemicals)
KW  - Survival of Motor Neuron 2 Protein (NLM Chemicals)
KW  - SMN2 protein, human (NLM Chemicals)
KW  - SMN1 protein, human (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C2  - pmc:PMC11384962
C6  - pmid:39067446
DO  - DOI:10.1016/j.xcrm.2024.101659
UR  - https://pub.dzne.de/record/271722
ER  -