Clumps of proteins twisted into aberrant shapes cause the prion diseases that have perplexed biologists for decades. The surprises just keep coming with a new report that the simple clusters of proteins responsible for Mad Cow and other prions diseases may, without help from DNA or RNA, be capable of changing form to escape the predations of drugs that target their eradication. Prion drug resistance could be eerily similar to that found in cancer and HIV—and may have implications for drug development for Alzheimer’s and Parkinson’s, neurodegenerative diseases also characterized by misfolded proteins.
Prion diseases include scrapie, chronic wasting disease and bovine spongiform encephalopathy (mad cow disease) in nonhuman species, and Creutzfeldt-Jakob disease and fatal insomnia in humans. They are unusual in that they can arise spontaneously, as a result of genetic mutations, or, in some instances, through infection. Remarkably, the infectious agent is not a microbe or virus, but rather the prion itself, a clump of proteins without genetic material.
The noxious agents originate when a normally generated protein – called the prion protein – mistakenly folds into a stable, sticky, and potentially toxic shape. When the misfolded protein contacts other prion protein molecules, they too are corrupted and begin to bind to one another. In the ensuing chain reaction, the prions grow, break apart, and spread; within the nervous system, they relentlessly destroy neurons, ultimately, and invariably, leading to death.
The surprising finding in the Oct 13 Proceedings of the National Academy of Sciences reveals that these non-living proteins undergo a kind of Darwinian selection when attacked by drugs. In their report, David Berry, Kurt Giles and their colleagues in the laboratory of Stanley Prusiner at the University of California San Francisco demonstrate that experimental drugs developed to slow the propagation of prions eventually select for resistant strains of prions. In forming prions, a protein can fold into subtly different three-dimensional structures, called strains, which influences their ability to cause disease.
In the experiment, the drugs used, IND24 and IND81, prolong the survival of prion-infected mice, apparently by delaying the proliferation of prions. With time, however, drug-resistant prions take over and the disease proceeds apace, much like the emergence of drug-resistant cancer cells following chemotherapy. Surprisingly, when the drug-resistant prions are transferred to untreated mice, the prions in the new hosts can revert to their former, drug-sensitive state.
At first blush, these findings might seem discouraging for the prospects of a cure—no drugs have yet been approved for clinical use, though a number of candidates are in development. Knowledge is power, though, and an understanding of strain selection in pathological proteins has key implications for the development of therapies.
To thwart resistant strains, multiple drugs with different modes of antiprion activity could be required. Another treatment option might be to minimize damage to cells. As the prions accumulate, stressed cells attempt to protect themselves by temporarily shutting down protein synthesis. If the shutdown is prolonged, vital proteins for normal cell metabolism become critically scarce and the cells malfunction and die. Very recently, Julie Moreno, Giovanna Mallucci and co-workers reported in Science Translational Medicine that an experimental drug that restores protein synthesis can impede neurodegeneration and delay the onset of prion disease in mouse models. Conceptually, this type of strategy – protecting neurons even as prions proliferate – clearly has therapeutic potential, but eventually, a truly disease-modifying treatment must de-fang the prions themselves. To do this will require a deeper appreciation of the Hydra-like nature of these extraordinary agents.
What is learned from these studies also could illuminate the pathway to therapeutics for other disorders. Common, non-infectious neurodegenerative diseases such as Alzheimer’s, Parkinson’s, Huntington’s, and ALS all involve the misfolding and aggregation of specific proteins in the nervous system, and in some instances the culpable proteins, like prions, can misfold into structurally distinct strains. Investigators trying to come to grips with the full panoply of diseases caused by misfolded proteins might help ensure the effectiveness of eventual therapies by heeding these first signs that a new form of drug resistance could undermine drug developers’ best efforts.
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