Novel survivin mutant protects differentiated SK-N-SH human neuroblastoma cells from activated T-cell neurotoxicity.
Currently, there are no known treatments for protection of axonal loss associated with neuroinflammatory diseases such as multiple sclerosis (MS). Survivin is a member of the inhibitors of the apoptosis (IAP) family of proteins that its neuroprotective effects have not been studied. We demonstrate here that SurR9-C84A, a survivin mutant, exhibits a neuroprotective role against the cytotoxic effects of activated T-cell infiltrates, such as granzyme B (GrB). The activated T-cell supernatants induce toxicity on differentiated SK-N-SH cells, which is associated with the loss of Ca(2+) homeostasis, the increased population of dead cells, mitochondrial membrane depolarisation, and the accelerated expression of cyclinD1, caspase3 and Fas, as observed for most apoptotic cells. Alternatively, the pre-treatment with SurR9-C84A reduces the population of dead cells by balancing the cytosolic Ca(2+) homeostasis, decreasing the level of mitochondrial depolarisation, and also reducing the expression of cyclinD1 and caspase3. Our findings suggest that SurR9-C84A has a neuroprotective effect against the cytotoxins existing in activated T-cell supernatants including GrB.
Laboratory of Immunology and Molecular Biomedical Research, Centre for Biotechnology and Interdisciplinary Biosciences (BioDeakin), Institute for Technology Research and Innovation (ITRI), Deakin University, Waurn Ponds, Victoria 3217, Australia.
Sara
S
Baratchi
Rupinder K
RK
Kanwar
Jagat R
JR
Kanwar
D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics* / Q000502:physiology / Q000627:therapeutic use; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D009103:Multiple Sclerosis / Q000235:genetics / Q000276:immunology / Q000517:prevention & control; D009154:Mutation / Q000235:genetics*; D009410:Nerve Degeneration / Q000235:genetics / Q000276:immunology / Q000517:prevention & control*; D009447:Neuroblastoma / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D000077022:Survivin; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology
C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D018696:Neuroprotective Agents; D000077022:Survivin