The role of ubiquitin-protein ligases in neurodegenerative disease

Alzheimer's disease and Parkinson's disease are the most common neurodegenerative conditions associated with the ageing process. The pathology of these and other neurodegenerative disorders, including polyglutamine diseases, is characterised by the presence of inclusion bodies in brain tissue of affected patients. In general, these inclusion bodies consist of insoluble, unfolded proteins that are commonly tagged with the small protein, ubiquitin. Covalent tagging of proteins with chains of ubiquitin generally targets them for degradation. Indeed, the ubiquitin/proteasome system (UPS) is the major route through which intracellular proteolysis is regulated. This strongly implicates the UPS in these disease-associated inclusions, either due to malfunction (of specific UPS components) or overload of the system (due to aggregation of unfolded/mutant proteins), resulting in subsequent cellular toxicity. Protein targeting for degradation is a highly regulated process. It relies on transfer of ubiquitin molecules to the target protein via an enzyme cascade and specific recognition of a substrate protein by ubiquitin-protein ligases (E3s). Recent advances in our knowledge gained from the Human Genome Mapping Project have revealed the presence of potentially hundreds of E3s within the human genome. The discovery that parkin, mutations in which are found in at least 50% of patients with autosomal recessive juvenile parkinsonism, is an E3 further highlights the importance of the UPS in neurological disease. To date, parkin is the only E3 confirmed to have a direct causal role in neurodegenerative disorders. However, a number of other (putative) E3s have now been identified that may cause disease directly or interact with neurological disease-associated proteins. Many of these are either lost or mutated in a given disease or fail to process disease-associated mutant proteins correctly. In this review, we will discuss the role(s) of E3s in neurodegenerative disorders.