Caspases in p75-mediatedCaspases in p75-mediatedNeuronal Death PathwayNeuronal Death Pathway

Cell Death

• Necrosis– Response to disease– Inflammatory Response

• Apoptosis– Present in Developing Tissue– Absence of Inflammatory Response– Mediated by certain pathways

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

p75-Mediated Pathway

N

G

F

Neuronal Death

NGF binds to the p75 receptor. This death receptor initiates the mitochondrial pathway for cell death.

MembraneMembrane

p75

N

G

F

Neuronal Death

The binding then causes the blocking of certain mitochondrial molecules such as BCL-2. This then allows cytochrome C to leave the mitochondrion.

Cyt C

Cyt C

Cyt CCyt C

Cyt C

Cyt C

N

G

F

Neuronal Death

Cytochrome C and apaf1, an adaptor protein, bind and activate caspase 9.

Cyt C

Apaf 1

C9

N

G

F

Neuronal Death

At the same time that Cytochrome C is being released, the mitochondrion also releases Smac/Diablo. S/D blocks MIAP.

C9

Cyt C Apaf 1

Smac/Diablo

MIAP

N

G

F

Neuronal Death

Caspase 9 activation leads to the activation of caspase 6 and 3.

C9Cyt C Apaf 1

Smac/Diablo

MIAP

C6

C3

N

G

F

Neuronal Death

Activation of Caspase 3 and Caspase 6 leads to neuronal death.

C9Cyt C Apaf 1

Smac/Diablo

MIAP

C6

C3

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

N

G

F

Neuronal Death

MIAP

C6

C3

1. p75 bound and there is no excitation between C3 and C6. What are the conditions for the cell to live?

2. p75 bound and there is excitation between C3 and C6. What are the conditions for the cell to die?

First Model: Vary Connection Between C6 and C3

N

G

F

Neuronal Death

MIAP

C6

C3

1. p75 bound the connection between p75 and C6 is absent. What are the conditions for the cell to live?

2. p75 bound the connection between p75 and C6 is present. What are the conditions for the cell to die?

Second Model: No Excitation Present Between C6 and C3 – Vary connection

between p75 and C6