Prions became infamous once scientists linked them with neurodegenerative disorders. Now scientists discover that prions can develop resistance to drugs, potentially complicating efforts to fight the diseases they cause, report findings detailed in the Proceedings of the National Academy of Sciences.
Recent evidence suggests the misfolded proteins known as prions are linked with many neurodegenerative diseases, including Alzheimer’s and Parkinson’s diseases. The best understood prion diseases are arguably those caused by the first prion protein identified, PrP — in humans, this includes Creutzfeldt–Jakob disease and kuru, and in animals, this includes scrapie, bovine spongiform encephalopathy (more commonly known as mad cow disease), and chronic wasting disease. Two versions of this protein can exist in the body — the normal cellular form, PrPC, and the misfolded disease-causing form, PrPSc.
So far no medicines exist that can halt or even slow neurodegeneration, which is invariably fatal. In their search for cures, scientists tested two potential therapeutics against prions, IND24 and IND81, on mice infected with Rocky Mountain Laboratory (RML) prions, a strain derived from scrapie. Although both compounds extended the lifespans of infected mice up to twofold, the rodents eventually succumbed to the disease and died.
To find out why these compounds did not protect the infected mice, the researchers analyzed their brains, focusing on rodents treated with IND24, since it consistently led to longer survival times compared with IND81. Surprisingly, they found that an IND24-resistant prion strain could emerge quickly during incubation experiments of mice treated with IND24.
“Successful treatments, treatments that double the survival of infected animals, can produce drug-resistant prions from a previously sensitive strain,” says study lead author David Berry, a molecular biologist at the University of California, San Francisco.
The normal strain of RML prions infects both N2A cells, which are nerve cell tumor cells, and CAD5 cells, a cell line derived from mouse neurons. In contrast, the IND24-resistant prion strain, dubbed RML[IND24], could only infect CAD5 cells. Prior studies found CAD5 cells can get infected by a wider range of prion strains than N2a cells.
When the CAD5 cells infected with IND24-resistant prions were treated with IND24, they were resistant to high concentrations of IND24. Intriguingly, after IND24-resistant prions were incubated in untreated mice, and re-isolated, these prions were susceptible to IND24 again.
These findings suggest that prion strains can acquire resistance upon exposure to drugs, but these strains can lose this resistance when they are incubated in untreated mice. This finding hints that continuous treatment with single anti-prion drugs can induce resistance; the researchers speculated that intermittent therapies with cocktails of several anti-prion drugs might be needed to slow or stop neurodegeneration, and limited the development of resistance, Berry said.
“There are a number of unanswered questions that this study may let us start to investigate,” Berry adds. “We want to understand more about the drug-resistant strain — is it generated by drug-treatment, or are we selecting among variant prions that already exist in low numbers?” The researchers are also working to figure out how the anti-prion compounds they developed work.