Serpinopathies and the conformational dementias

Nat Rev Genet. 2002 Oct;3(10):759-68. doi: 10.1038/nrg907.


The serpin superfamily of serine proteinase inhibitors has a central role in controlling proteinases in many biological pathways in a wide range of species. The inhibitory function of the serpins involves a marked conformational transition, but this inherent molecular flexibility also renders the serpins susceptible to point mutations that result in aberrant intermolecular linkage and polymer formation. The effects of such protein aggregation are cumulative, with a progressive loss of cellular function that results in diseases as diverse as cirrhosis and emphysema. The recent recognition that mutations in a serpin can also result in late-onset dementia provides insights into changes that underlie other conformational diseases, such as the amyloidoses, the prion encephalopathies and Huntington and Alzheimer diseases.

Publication types

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

MeSH terms

  • Amyloid / metabolism
  • Animals
  • Dementia / etiology*
  • Dementia / genetics
  • Dementia / metabolism
  • Drug Design
  • Humans
  • Huntingtin Protein
  • Inclusion Bodies / genetics
  • Models, Molecular
  • Mutation
  • Nerve Tissue Proteins / metabolism
  • Neurodegenerative Diseases / etiology*
  • Neurodegenerative Diseases / genetics
  • Neurodegenerative Diseases / metabolism
  • Neuropeptides / metabolism
  • Nuclear Proteins / metabolism
  • Prions / metabolism
  • Protein Conformation
  • Serpins / chemistry
  • Serpins / genetics*
  • Serpins / metabolism


  • Amyloid
  • HTT protein, human
  • Huntingtin Protein
  • Nerve Tissue Proteins
  • Neuropeptides
  • Nuclear Proteins
  • Prions
  • Serpins
  • neuroserpin