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.