Caspases in p75-mediated Neuronal Death Pathway - PowerPoint PPT Presentation

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Caspases in p75-mediated Neuronal Death Pathway

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Caspases in p75-mediated Neuronal Death Pathway

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  1. Caspases in p75-mediatedNeuronal Death Pathway

  2. Cell Death • Necrosis • Response to disease • Inflammatory Response • Apoptosis • Present in Developing Tissue • Absence of Inflammatory Response • Mediated by certain pathways

  3. Details of the p75-mediated Cell Death Pathway • NGF • p75 Receptor • Mitochondria (Cytochrome C, Adaptor Protein-Apaf1, & Smac/Diablo) • MIAP3 • Caspase 9 • Caspase 6 • Caspase 3

  4. p75-Mediated Pathway

  5. NGF binds to the p75 receptor. This death receptor initiates the mitochondrial pathway for cell death. N G F p75 Membrane Neuronal Death

  6. The binding then causes the blocking of certain mitochondrial molecules such as BCL-2. This then allows cytochrome C to leave the mitochondrion. N G F Cyt C Cyt C Cyt C Cyt C Cyt C Cyt C Neuronal Death

  7. Cytochrome C and apaf1, an adaptor protein, bind and activate caspase 9. N G F C9 Cyt C Apaf 1 Neuronal Death

  8. At the same time that Cytochrome C is being released, the mitochondrion also releases Smac/Diablo. S/D blocks MIAP. N G F C9 Cyt C Apaf 1 Smac/Diablo MIAP Neuronal Death

  9. Caspase 9 activation leads to the activation of caspase 6 and 3. N G F C9 C6 C3 Cyt C Apaf 1 Smac/Diablo MIAP Neuronal Death

  10. Activation of Caspase 3 and Caspase 6 leads to neuronal death. N G F C9 C6 C3 Cyt C Apaf 1 Smac/Diablo MIAP Neuronal Death

  11. How did we simplify the pathway for a math model? • Group cellular events together • Caspases 9 and 6 • Eliminate upstream regulatory proteins • Cyt C, Apaf 1, Smac/Diablo

  12. N G F C6 C3 First Model: Vary Connection Between C6 and C3 • p75 bound and there is no excitation between C3 and C6. What are the conditions for the cell to live? • p75 bound and there is excitation between C3 and C6. What are the conditions for the cell to die? MIAP Neuronal Death

  13. N G F C6 C3 Second Model: No Excitation Present Between C6 and C3 – Vary connection between p75 and C6 • p75 bound the connection between p75 and C6 is absent. What are the conditions for the cell to live? • p75 bound the connection between p75 and C6 is present. What are the conditions for the cell to die? MIAP Neuronal Death