Between the sixties and eighties,most life scientists focused their attention on studies of nucleic acids and the translation of the coded information.Protein degradation was a neglected area,considered to be a non-specific,dead-end process.While it was known that proteins do turn over,the large extent and high specificity of the process whereby distinct proteins have half-lives that range from a few minutes to several days-was not appreciated.The discovery of the lysosome by Christian de Duve did not significantly change this view,as it was clear that this organelle is involved mostly in the degradation of extracellular proteins,and their proteases cannot be substrate specific.The discovery of the complex cascade of the ubiquitin pathway revolutionized the field.It is clear now that degradation of cellular proteins is a highly complex,temporally controlled,and tightly regulated process that plays major roles in a variety of basic pathways during cell life and death,and in health and disease.With the multitude of substrates targeted,and the myriad processes involved,it is not surprising that aberrations in the pathway are implicated in the pathogenesis of many diseases,certain malignancies and neurodegeneration among them.