Relevance of death receptors in nervous system: role in the pathogenesis of neurodegenerative diseases and targets for therapy

Abstract

Apoptosis is a strictly controlled, physiological process by which the number of cells in metazoan organisms is regulated. Recently, it has been shown that apoptosis is involved in the pathogenesis of certain nervous system diseases. Excess cell death is thought to contribute to neurodegenerative disorders while defects in apoptosis lead to the development of neoplasias. Regulation of apoptosis primarily occurs through the activation of caspases, cysteine proteases that specifically cleave aspartic acid residues. Caspases are activated by two mechanisms: (1) release of cytochrome C from mitochondria to the cytoplasm and (2) activation of plasma membrane death receptors (DRs). These latter proteins have been widely characterized in the immune system, whereas in the nervous system their function remains elusive. In this article we focus on the role of DRs in the pathogenesis of neurodegenerative diseases and on the potential of these proteins as therapeutic targets. We also discuss several intracellular molecules that modulate DR activation. Among these, we introduce two novel proteins, Lifeguard and FAIM, which are specifically expressed in the nervous system.