Characterization of a p75NTR Apoptotic Signaling Pathway Using a Novel Cellular Model

Abstract

The p75 neurotrophin receptor (p75NTR) belongs to the tumor necrosis factor 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 striatal neurons, in which the expression of p75NTR is inducibly controlled by the ecdysone receptor. In these cells p75NTR induces apoptosis through 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 dominant negative form of caspase 9 and Bcl-XL consistent with a pathway that involves mitochondria. Significantly, the viral flice inhibitory protein E8 protects from p75NTR-induced cell death indicating that death effector domains are involved. A p75NTR construct with a deleted death domain dominantly interferes with p75 NTR signaling, implying that receptor multimerization is required. However, in contrast to the other receptors of the family, p75 NTR-mediated apoptosis does not involve the adaptor proteins Fas-associated death domain protein or tumor necrosis factor-associated death domain protein, and the apical caspase 8 is not activated. We conclude that p75NTR signals apoptosis by similar mechanisms as other death receptors but uses different adaptors and apical caspases.