Elsevier

The Lancet

Volume 350, Issue 9071, 12 July 1997, Pages 134-138
The Lancet

Review
Conformational disease

https://doi.org/10.1016/S0140-6736(97)02073-4Get rights and content

Summary

Several diverse disorders, including the prevalent dementias and encephalopathies, are now believed to arise from the same general disease mechanism. In each, there is abnormal unfolding and then aggregation of an underlying protein. The gradual accumulation of these aggregates and the acceleration of their formation by stress explain the characteristic late or episodic onset of the clinical disease. The understanding of these processes at the molecular level is opening prospects of more rational approaches to investigation and therapy.

Section snippets

Prion proteins

It is now believed that the spongiform encephalopathies are due to a conformational change, with consequent self-association, in the prion proteins of the brain.4 Although the structural details are not known, the proposed change involves a transition from a primarily helical structure5 to a primarily β-sheet structure—as shown diagrammatically6 in figure la. This conformational change in prion proteins can occur spontaneously as a result of a genetic mutation in the prion—as in the rare

Conclusion

The grouping of diseases on the basis of their abnormalities provides a better understanding of what are often diverse clinical presentations. Such categorisation is seldom clear-cut, and the conformational abnormalities can range in severity from the most gross forms with misfolding at synthesis and a consequent straightforward genetic deficiency. Here we have reserved the concept of conformational disease for the more subtle folding defects, which are compatible with normal production of a

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