Journal Article

DZNE-2024-01074

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Isogenic patient-derived organoids reveal early neurodevelopmental defects in spinal muscular atrophy initiation.

Grass, T. (First author)DZNE* ; Dokuzluoglu, Z.DZNE* ; Buchner, F.DZNE* ; Rosignol, I.DZNE* ; Thomas, J.DZNE* ; Caldarelli, A.DZNE* ; Dalinskaya, A.DZNE* ; Becker, J. ; Rost, F. ; Marass, M. ; Wirth, B. ; Beyer, M.DZNE* ; Bonaguro, L.DZNE* ; Rodriguez-Muela, N. (Last author)DZNE*

2024
Elsevier Maryland Heights, MO

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Please use a persistent id in citations: doi:10.1016/j.xcrm.2024.101659

Abstract: 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.

Keyword(s): Organoids: pathology (MeSH) ; Organoids: metabolism (MeSH) ; Humans (MeSH) ; Muscular Atrophy, Spinal: pathology (MeSH) ; Muscular Atrophy, Spinal: genetics (MeSH) ; Muscular Atrophy, Spinal: metabolism (MeSH) ; Induced Pluripotent Stem Cells: metabolism (MeSH) ; Induced Pluripotent Stem Cells: pathology (MeSH) ; Motor Neurons: pathology (MeSH) ; Motor Neurons: metabolism (MeSH) ; Survival of Motor Neuron 1 Protein: genetics (MeSH) ; Survival of Motor Neuron 1 Protein: metabolism (MeSH) ; Survival of Motor Neuron 2 Protein: genetics (MeSH) ; Survival of Motor Neuron 2 Protein: metabolism (MeSH) ; Animals (MeSH) ; Mice (MeSH) ; Spinal Cord: pathology (MeSH) ; Spinal Cord: metabolism (MeSH) ; Neural Stem Cells: metabolism (MeSH) ; Neural Stem Cells: pathology (MeSH) ; isogenic SMA model ; neurodevelopmental defects ; neuromesodermal progenitors ; organoids ; spinal cord ; Survival of Motor Neuron 1 Protein ; Survival of Motor Neuron 2 Protein ; SMN2 protein, human ; SMN1 protein, human

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Contributing Institute(s):

1. Selective Neuronal Vulnerability in Neurodegenerative Diseases (AG Rodriguez-Muela)
2. Immunogenomics and Neurodegeneration (AG Beyer)
3. Clinical Single Cell Omics (CSCO) / Systems Medicine (AG Schultze)
4. Platform for Single Cell Genomics and Epigenomics (PRECISE)

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)
2. 351 - Brain Function (POF4-351) (POF4-351)
3. 354 - Disease Prevention and Healthy Aging (POF4-354) (POF4-354)

Experiment(s):

1. Platform for Single Cell Genomics and Epigenomics at DZNE University of Bonn

Appears in the scientific report 2024

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