Isogenic patient-derived organoids reveal early neurodevelopmental defects in spinal muscular atrophy initiation

• DOI: 10.1016/j.xcrm.2024.101659
• Publication Date: 2024-07-26T21:58:29Z
• Authors: Tobias Grass; Zeynep Dokuzluoglu; Felix Buchner; Ines Rosignol; Joshua Thomas; Antonio Caldarelli; Anna Dalinskaya; Jutta Becker; Fabian Rost; Michele Marass; Brunhilde Wirth; Marc Beyer; Lorenzo Bonaguro; Natalia Rodriguez...
• Keywords: isogenic SMA model; metabolism [Spinal Cord]; metabolism [Organoids]; pathology [Motor Neurons]; Induced Pluripotent Stem Cells; pathology [Spinal Cord]; metabolism [Neural Stem Cells]; pathology [Neural Stem Cells]; metabolism [Survival of Motor Neuron 1 Protein]; genetics [Muscular Atrophy, Spinal]; Article; metabolism [Survival of Motor Neuron 2 Protein]; Muscular Atrophy, Spinal; Mice; SMN2 protein, human; genetics [Survival of Motor Neuron 2 Protein]; Neural Stem Cells; Humans; Animals; ddc:610; organoids; Motor Neurons; pathology [Organoids]; neurodevelopmental defects; neuromesodermal progenitors; spinal cord; metabolism [Motor Neurons]; genetics [Survival of Motor Neuron 1 Protein]; pathology [Induced Pluripotent Stem Cells]; Survival of Motor Neuron 1 Protein; metabolism [Induced Pluripotent Stem Cells]; Organoids; Survival of Motor Neuron 2 Protein; Spinal Cord; SMN1 protein, human; metabolism [Muscular Atrophy, Spinal]; pathology [Muscular Atrophy, Spinal]

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.