Ubiquitin, cellular inclusions and their role in neurodegeneration

Trends Neurosci. 1998 Dec;21(12):516-20. doi: 10.1016/s0166-2236(98)01276-4.


Covalent binding of ubiquitin to proteins marks them for degradation by the ubiquitin/ATP-dependent pathway. This pathway plays a major role in the breakdown of abnormal proteins that result from oxidative stress, neurotoxicity and mutations. Failure to eliminate ubiquitinated proteins disrupts cellular homeostasis, causing degeneration. Inclusions containing ubiquitinated proteins are commonly detected in many neurological disorders. These aggregates are mostly cytosolic; nevertheless, ubiquitinated inclusions are found 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 aggregates must result from a malfunction or overload of the ubiquitin/ATP-dependent pathway or from structural changes in the protein substrates, halting their degradation. Prevention of protein aggregation in these diseases might offer new therapeutic leads.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.
  • Review

MeSH terms

  • Animals
  • Endosomes / metabolism
  • Humans
  • Inclusion Bodies / physiology*
  • Lysosomes / metabolism
  • Models, Molecular
  • Mutation
  • Neurodegenerative Diseases / metabolism
  • Neurodegenerative Diseases / physiopathology*
  • Neurons / metabolism
  • Neurons / physiology
  • Reactive Oxygen Species / metabolism
  • Ubiquitins / physiology*


  • Reactive Oxygen Species
  • Ubiquitins