Progress made on the long road to untangling protein aggregation.

Progress made on the long road to untangling protein aggregation.

Baker’s yeast cannot catch mad cow disease, but the single cell organism also has proteins whose misfolding can be inherited in ways independent of DNA. The translation termination factor Sup35, for instance, can fold into an alternative shape that triggers other molecules to do the same, and it is therefore known as a yeast prion and studied as a simple and harmless model system for the molecular processes in prion conversion.

Susan Lindquist, currently director of the Whitehead institute for Biomedical Research in Cambridge, MA, US, has been involved in yeast prion research from the beginning. Her group has now combined this system with the molecular chaperone Hsp104 and obtained some surprising results. Hsp104 and its close relatives are unique among the heat shock proteins in that they not only help to avoid misfolding and aggregation, but even disaggregate certain kinds of misfolded proteins. If this capability extended to the amyloid lumps formed in prion diseases, Alzheimer’s and Parkinson’s disease, that might be of considerable medical importance.

Surprisingly, Lindquist and James Shorter found that the effect of Hsp104 on the propagation of yeast prions is strongly dosage dependent. At low concentrations, the chaperone helps to expose ’infectious’ misfolded surfaces, thereby catalysing the formation of more prions and amyloid fibrils. At high concentrations, however, it stops the formation of fibrils and disassembles existing aggregates, thereby eliminating prion propagation altogether.

In the absence of Hsp104, uncatalysed prion conversion remains slow and inefficient.

These findings go a long way to explaining the inheritance patterns of yeast prions, but a drug that disaggregates amyloid in humans remains a distant hope.

Michael Gross