The ubiquitin protein catabolic disorders

The ubiquitin-proteasome system of intracellular proteolysis is essential f or cell viability. We propose the concept that neurodegenerative diseases s uch as Alzheimer's and Parkinson's, as well as other conditions including s ome types of cancer, collectively represent a raft of 'ubiquitin protein ca tabolic disorders' in which altered function of the ubiquitin-proteasome sy stem can cause or directly contribute to disease pathogenesis. Genetic abno rmalities within the ubiquitin pathway, either in ubiquitin-ligase (E3) enz ymes or in deubiquitinating enzymes, cause disease because of problems asso ciated with substrate recognition or supply of free ubiquitin, respectively . In some cases, mutations in protein substrates of the ubiquitin-proteasom e system may directly contribute to disease progression because of ineffici ent substrate recognition. Mutations in transcripts for the ubiquitin prote in itself (as a result of 'molecular misreading') also affect ubiquitin-dep endent proteolysis with catastrophic consequences. This has been shown in A lzheimer's disease and could apply to other age-associated neurodegenerativ e conditions. Within the nervous system, accumulation of unwanted proteins as a result of defective ubiquitin-dependent proteolysis may contribute to aggregation events, which underlie the pathogenesis of several major human neurodegenerative diseases.