Abstract
Prions are the agent responsible for a group of transmissible and inevitably fatal
neurodegenerative disease in humans and other mammals. Prion disease is caused by
the misfolding of a host encoded protein, PrPC, into the infectious conformation PrPSc.
Phenotypic differences in disease (i.e., strains) have been observed for decades and
are thought to be encoded by stain-specific conformations of PrPSc. There is evidence
that prion strains exist as a mixture of multiple strains, containing a dominant strain,
which is responsible for the phenotype, and suppressed populations of substrains.
However, direct evidence for the presence of substrains has been difficult to establish,
due in part to strain interference and limited detection methods.
It is hypothesized that prions propagate as dynamic strain mixtures. Utilizing
experimentally feasible methods, we provide evidence for prions consisting of a
dominant strain and substrains. We show that the improved sensitivity of the in vitro
amplification method called protein misfolding cyclic amplification (PMCA) allows for
detection of minute quantities of PrPSc. Combined with differences in conformational
stability between strains which allow for the selective amplification and detection of
biochemically distinct substrains.
There are important implications for stains existing as mixtures. Namely,
increased zoonotic disease potential, and the possible emergence of drug resistant
prions with the use of targeted anti-prion agents. These data inform our understanding
of prions and the zoonotic potential for disease and prion adaptation in the presence of
anti-prion drugs. Overall, these investigations improve our understanding of the dynamic
nature of prion strains.