Inhibition of apoptosis blocks human motor neuron cell death in a stem cell model of spinal muscular atrophy

• Published in: PloS one Vol. 7; no. 6; p. e39113
• Main Authors: Sareen, Dhruv, Ebert, Allison D, Heins, Brittany M, McGivern, Jered V, Ornelas, Loren, Svendsen, Clive N
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 19-06-2012; Public Library of Science (PLoS)
• Subjects: Amyotrophic lateral sclerosis; Antibodies, Monoclonal - pharmacology; Apoptosis; Apoptosis - drug effects; Apoptosis - genetics; Atrophy; Biology; Biomarkers; Blocking antibodies; Caspase; Caspase 8 - metabolism; Caspase-3; Caspase-8; Cell culture; Cell Culture Techniques; Cell death; Cell Differentiation; Cell Line; Cell survival; Chemokines; Clonal deletion; Cloning; Comparative analysis; Disease; Enzyme Activation; Fas Ligand Protein - metabolism; fas Receptor - antagonists & inhibitors; FasL protein; Fibroblasts; Gene deletion; Gene expression; Gene Expression Regulation - drug effects; Genetic disorders; Heat shock proteins; Humans; Induced Pluripotent Stem Cells - cytology; Induced Pluripotent Stem Cells - drug effects; Induced Pluripotent Stem Cells - metabolism; Melatonin; Motor neurons; Motor Neurons - cytology; Motor Neurons - drug effects; Motor Neurons - metabolism; Muscles; Muscular Atrophy, Spinal - genetics; Muscular Atrophy, Spinal - metabolism; Neurobiology; Neuromuscular diseases; Neurons; Neurosciences; Paralysis; Phenotype; Pluripotency; Protein expression; Rodents; Spinal muscular atrophy; Stem cells; Tumor necrosis factor-TNF; Viruses; Los Angeles California; California; United States > US; Wisconsin
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0039113

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.