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

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. [Display omitted] •Cohort of isogenic control patient-derived SMA iPSC lines•Accelerated differentiation of SMA spinal motor neurons•Neuromesodermal fate commitment defects in SMA spinal cord organoids•Mesodermal bias of neuromesodermal progenitors in early SMA mouse embryos Neurodegenerative diseases are often investigated from a postnatal perspective, ignoring the potential contribution of developmental aspects. Using a spinal cord organoid model derived from isogenic SMA iPSCs, Grass et al. uncover the role of SMN in neuronal progenitor and mesodermal specification. These developmental impairments precede the neuronal loss characteristic of SMA.