Characterization of a p75(NTR) apoptotic signaling pathway using a novel cellular model

The p75 neurotrophin receptor (p75(NTR)) belongs to the tumor necrosis fact or receptor/nerve growth factor receptor superfamily. In some cells derived from neuronal tissues it causes cell death through a poorly characterized pathway. We developed a neuronal system using conditionally immortalized st riatal neurons, in which the expression of p75(NTR) is inducibly controlled by the ecdysone receptor. In these cells p75(NTR) induces apoptosis throug h its death domain in a nerve growth factor-independent manner. Caspases 9, 6, and 3 are activated by receptor expression indicating the activation of the common effector pathway of apoptosis. Cell death is blocked by a domin ant negative form of caspase 9 and Bcl-X-L consistent with a pathway that i nvolves mitochondria. Significantly, the viral flice inhibitory protein E8 protects from p75(NTR). induced cell death indicating that death effector d omains are involved. A p75(NTR) construct with a deleted death domain domin antly interferes with p75(NTR) signaling, implying that receptor multimeriz ation is required. However, in contrast to the other receptors of the famil y, p76(NTR)-mediated apoptosis does not involve the adaptor proteins Fas-as sociated death domain protein or tumor necrosis factor-associated death dom ain protein, and the apical caspase 8 is not activated. We conclude that p7 5(NTR) signals apoptosis by similar mechanisms as other death receptors but uses different adaptors and apical caspases.