Inhibition of apoptosis blocks human motor neuron cell death in a stem cell model of spinal muscular atrophy. PLoS One 2012;7(6):e39113
Date
06/23/2012Pubmed ID
22723941Pubmed Central ID
PMC3378532DOI
10.1371/journal.pone.0039113Scopus ID
2-s2.0-84862518720 (requires institutional sign-in at Scopus site) 126 CitationsAbstract
Spinal muscular atrophy (SMA) is a genetic disorder caused by a deletion of the survival motor neuron 1 gene leading to motor neuron loss, muscle atrophy, paralysis, and death. We show here that induced pluripotent stem cell (iPSC) lines generated from two Type I SMA subjects-one produced with lentiviral constructs and the second using a virus-free plasmid-based approach-recapitulate the disease phenotype and generate significantly fewer motor neurons at later developmental time periods in culture compared to two separate control subject iPSC lines. During motor neuron development, both SMA lines showed an increase in Fas ligand-mediated apoptosis and increased caspase-8 and-3 activation. Importantly, this could be mitigated by addition of either a Fas blocking antibody or a caspase-3 inhibitor. Together, these data further validate this human stem cell model of SMA, suggesting that specific inhibitors of apoptotic pathways may be beneficial for patients.
Author List
Sareen D, Ebert AD, Heins BM, McGivern JV, Ornelas L, Svendsen CNAuthor
Allison D. Ebert PhD Center Director, Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Antibodies, MonoclonalApoptosis
Biomarkers
Caspase 8
Cell Culture Techniques
Cell Differentiation
Cell Line
Enzyme Activation
Fas Ligand Protein
Gene Expression Regulation
Humans
Induced Pluripotent Stem Cells
Motor Neurons
Muscular Atrophy, Spinal
Phenotype
fas Receptor
