BBB seminar: Dale E. Bredesen

Dale E. Bredesen
Buck Institute for Age Research, Novato, and University of California, San Francisco, CA, USA

Programmatic cell death (pcd) is an important aspect of development, neoplasia, and degeneration, among other processes. Genetic and biochemical studies of pcd have identified a set of morphologically and biochemically similar cell death pathways given the name apoptosis(2). Although the term apoptosis has often been used interchangeably with the term pcd, it has become clear that the morphological and biochemical descriptions of apoptosis are inadequate to describe all pcd. The biochemical basis for alternative, nonapoptotic forms of cell death remains largely unknown. Understanding the mechanisms for these forms has potentially important implications for the understanding of evolutionary aspects of cell death programs, developmental cell death, neurodegeneration, and cancer therapeutics.

Our initial approach taken to identify alternative forms of pcd was to identify receptors that induce cell death that fails to fulfill the criteria for apoptosis, and two such receptors were initially identified: the insulin-like growth factor I receptor (IGF1R) and NK1R, the neurokinin-1 receptor. These dissimilar receptors both mediate a non-apoptotic cell death program(s) that is transcription dependent, lacks caspase activation, lacks internucleosomal DNA cleavage, lacks morphological hallmarks of apoptosis such as nuclear fragmentation and swelling of the endoplasmic reticulum and mitochondria, and is not inhibited by caspase inhibitors or Bcl-xL. This alternative, non-apoptotic cell death program was dubbed paraptosis. Morphologically similar forms of cell death have been described in development, in neurodegeneration (in transgenic models of both amyotrophic lateral sclerosis and Huntington's disease), in excitotoxicity, and in some organisms whose origins predate the evolutionary appearance of caspases, such as Dictyostelium discoideum.

In order to identify the mediators of paraptosis, we have taken a combination of approaches that includes site-directed mutagenesis, protein interaction studies, gene expression microarray studies, and proteomics studies. In addition, we have compared other forms of pcd that are demonstrably distinct from apoptosis, autophagic pcd, and paraptosis. These ongoing studies will be described, as well as the identification of an inhibitor that blocks both caspase-dependent and caspase-independent forms of pcd. Our studies suggest that multiple programs of cell death are available to mammalian cells, and that these must be taken into account when developing therapeutics that modulate pcd.

Host: Anne Døskeland, Department of Biomedicine