Document Detail

Recapitulation of spinal motor neuron-specific disease phenotypes in a human cell model of spinal muscular atrophy.
MedLine Citation:
PMID:  23208423     Owner:  NLM     Status:  MEDLINE    
Establishing human cell models of spinal muscular atrophy (SMA) to mimic motor neuron-specific phenotypes holds the key to understanding the pathogenesis of this devastating disease. Here, we developed a closely representative cell model of SMA by knocking down the disease-determining gene, survival motor neuron (SMN), in human embryonic stem cells (hESCs). Our study with this cell model demonstrated that knocking down of SMN does not interfere with neural induction or the initial specification of spinal motor neurons. Notably, the axonal outgrowth of spinal motor neurons was significantly impaired and these disease-mimicking neurons subsequently degenerated. Furthermore, these disease phenotypes were caused by SMN-full length (SMN-FL) but not SMN-Δ7 (lacking exon 7) knockdown, and were specific to spinal motor neurons. Restoring the expression of SMN-FL completely ameliorated all of the disease phenotypes, including specific axonal defects and motor neuron loss. Finally, knockdown of SMN-FL led to excessive mitochondrial oxidative stress in human motor neuron progenitors. The involvement of oxidative stress in the degeneration of spinal motor neurons in the SMA cell model was further confirmed by the administration of N-acetylcysteine, a potent antioxidant, which prevented disease-related apoptosis and subsequent motor neuron death. Thus, we report here the successful establishment of an hESC-based SMA model, which exhibits disease gene isoform specificity, cell type specificity, and phenotype reversibility. Our model provides a unique paradigm for studying how motor neurons specifically degenerate and highlights the potential importance of antioxidants for the treatment of SMA.
Zhi-Bo Wang; Xiaoqing Zhang; Xue-Jun Li
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-12-04
Journal Detail:
Title:  Cell research     Volume:  23     ISSN:  1748-7838     ISO Abbreviation:  Cell Res.     Publication Date:  2013 Mar 
Date Detail:
Created Date:  2013-03-04     Completed Date:  2013-09-05     Revised Date:  2014-03-07    
Medline Journal Info:
Nlm Unique ID:  9425763     Medline TA:  Cell Res     Country:  England    
Other Details:
Languages:  eng     Pagination:  378-93     Citation Subset:  IM    
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MeSH Terms
Blotting, Western
Cell Differentiation / genetics,  physiology
Cell Line
Embryonic Stem Cells / cytology*,  metabolism*
Flow Cytometry
Motor Neurons / cytology*,  metabolism*
Muscular Atrophy, Spinal / genetics,  metabolism*,  pathology*
Protein Isoforms / genetics,  metabolism
Reverse Transcriptase Polymerase Chain Reaction
SMN Complex Proteins / genetics,  metabolism*
Survival of Motor Neuron 1 Protein / genetics,  metabolism
Survival of Motor Neuron 2 Protein / genetics,  metabolism
Reg. No./Substance:
0/Protein Isoforms; 0/SMN Complex Proteins; 0/Survival of Motor Neuron 1 Protein; 0/Survival of Motor Neuron 2 Protein

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