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¹ Department of Hematology, Oncology, and Molecular Medicine
² Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, 00161 Rome, Italy
³ Dipartimento di Biologia e Patologia Cellulare e Molecolare, Facoltà di Scienze Biotecnologiche, Federico II University of Naples, 80131 Naples, Italy
⁴ Laboratory of Neurobiology, Department of Neurobiology and Neurorestorative Therapies, National Neurological Institute "C. Besta"
⁵ Institute for Obstetric and Gynecology ‘‘L. Mangiagalli, ’’ ICP, 20126 Milan, Italy
⁶ Kimmel Cancer Institute, Thomas Jefferson University, Philadelphia, PA 19107
⁷ Mediterranean Institute of Oncology, 95030 Catania, Italy

Address correspondence to Ruggero De Maria, Dept. of Hematology, Oncology, and Molecular Medicine, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy. Phone: 39-06-4990-3121; Fax: 39-06-4938-7087; email: rdemaria{at}tin.it

The mechanisms that control neural stem and progenitor cell survival are unknown. In several pathological conditions, death receptor (DR) ligands and inflammatory cytokines exert a deleterious effect on neurons, whereas primitive neural cells migrate and survive in the site of lesion. Here, we show that even in the presence of inflammatory cytokines, DRs are unable to generate death signals in primitive neural cells. Neural stem and progenitor cells did not express caspase 8, the presence of which is required for initiating the caspase cascade. However, exogenous or cytokine-mediated expression of caspase 8 was not sufficient to restore their DR sensitivity. Searching for molecules potentially able to block DR death-inducing signaling complex (DISC), we found that primitive neural cells expressed high levels of the death effector domain-containing protein PED (also known as PEA-15). PED localized in the DISC and prevented caspase 8 recruitment and activation. Moreover, lentiviral-mediated delivery of PED antisense DNA resulted in dramatic down-regulation of the endogenous gene expression and sensitization of primitive neural cells to apoptosis mediated by inflammatory cytokines and DRs. Thus, absence of caspase 8 and high expression of PED constitute two levels of protection from apoptosis induced by DRs and inflammatory cytokines in neural stem and progenitor cells.

Key Words: neural stem cells • apoptosis • inflammatory cytokines • death receptors • death-inducing signaling complex

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