Prions are shape-shifting proteins that act like germs, infecting healthy tissue and causing havoc in the body. Prions pass on, or infect, by converting normally folded molecules of the same protein into abnormally structured clumps called amyloid. The changed structure is extremely stable and accumulates in infected tissue, causing tissue damage and cell death, often leading to devastating disorders in the brain, such as ‘mad cow’ disease. This extreme stability and the ability to shift into multiple different shapes or ‘strains’ make prions exceptionally difficult drug targets.

Yeast Prions

Yeast prions. Credit: James Shorter, PhD.

In a paper published in Nature Chemical Biology, researchers found that yeast prions were able to evade a small-molecule inhibitor by shifting into a novel drug-resistant shape that does not usually appear. However, by combining two small molecules, prions could no longer escape and were eradicated.

“We were very surprised to find that the prion could change into a brand new shape to evade what we had anticipated to be a very potent small molecule inhibitor. However, by combining two different inhibitors we were able to hit multiple prion strains.” says senior author James Shorter, PhD, assistant professor of Biochemistry and Biophysics at the Perelman School of Medicine.

These findings provide proof-of-principle that small molecule combinations can counter strains of amyloid, which likely plays an important role in other fatal neurodegenerative disorders, including Alzheimer’s and Huntington’s disease.

“When used together their effect was synergistic, because the two small molecules work in different ways to break up the prions. We suspect that small molecule cocktails that safely eradicate complete strain repertoires can be found for various neurodegenerative disorders.” says Shorter.

This research was done in collaboration with Martin Duennwald at the Boston Biomedical Research Institute.

 

This story appears in Penn Medicine's Basic Science News Bites (December 2009). Also in this edition:

  • Orthopaedics Research
  • picThrowing Their Backs into Regenerative Medicine
  • In order for tissue grown in the lab to replace damaged or diseased tissue in the body, it needs to withstand complex mechanical loads – large forces regularly experienced over a lifetime of daily activities.
  • Cell Biology
  • picCheating a Cell's Demise
  • The lifespan of normal human cells is determined in part by telomeres – the DNA-protein structures that cap the beginnings and ends of chromosomes.
  • Neuroscience Research
  • picPrion-Busting Cocktails
  • Prions are proteins that act like germs, infecting healthy tissue and causing havoc in the body. Their extreme stability and shape-shifting abilities make prions exceptionally difficult drug targets.
  • Diabetes Research
  • picNew Insights on Insulin Resistance
  • The overwhelming majority of type 2 diabetics are insulin resistant, which means their bodies are unable to respond to and use the insulin they produce.
  • Genetics Research
  • picZebrafish Model of Common Genetic Disorder
  • Because zebrafish develop rapidly, are transparent when young, and can be easily bred in large numbers, this new animal model will dramatically increase the screening capacity for a common human inherited disorder.

 

 

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