Ubiquitin, cellular inclusions and their role in neurodegeneration

Covalent binding of ubiquitin to proteins marks them for degradation by the ubiquitin/ATP-dependent pathway. This pathway plays a major role in the br eakdown of abnormal proteins that result from oxidative stress, neurotoxici ty and mutations. Failure to eliminate ubiquitinated proteins disrupts cell ular homeostasis, causing degeneration. Inclusions containing ubiquitinated proteins are commonly detected in many neurological disorders. These aggre gates are mostly cytosolic; nevertheless, ubiquitinated inclusions are foun d in endosomes/lysosomes in Alzheimer's disease and prion encephalopathies, and in nuclei in disorders associated with CAG/polyglutamine repeats, such as Huntington's disease and spinocerebellar ataxias. Ubiquitinated aggrega tes must result: from a malfunction or overload of the ubiquitin/ATP-depend ent pathway or from structural changes in the protein substrates, halting t heir degradation. Prevention of protein aggregation in these diseases might offer new therapeutic leads.