A team of investigators at several institutions, including the Whitehead Institute for Biomedical Research, the Howard Hughes Institute, MIT, and the University of Massachusetts Medical School, have developed novel mouse models for two fatal human prion protein (PrP) diseases, fatal familial insomnia (FFI) and Creutzfeldt-Jakob disease (CJD). The results of their study were published online this week in the Proceedings of the National Academy of Sciences.

To date, these fatal neurodegenerative diseases have been extremely difficult to study because of the lack of animal models that recapitulate the pathology and features of the diseases.

The study’s first author is Walker S. Jackson, Ph.D., of the Whitehead Institute. “Walker’s work provides two extraordinary models of neurodegeneration,” said Susan Lindquist, Ph.D., who is a professor of biology at MIT and in whose lab part of the work was performed. “Most mouse models produce pathology that only distantly resembles human diseases. These nail it, for two of the most enigmatic human diseases in the world.”

The prion hypothesis, which originated in 1982 with Stanley B. Prusiner, M.D., of the University of California School of Medicine at San Francisco, holds that prion diseases, including “mad cow” disease (bovine spongiform encephalopathy) and scrapie in sheep, are caused by a protein that has adopted an abnormal form. According to the prion hypothesis, PrPs infect by passing along their misfolded shape in templated fashion, unlike viruses or bacteria, which depend on DNA or RNA to transmit their information. Certain changes to the prion create a misshapen structure, which is replicated by contact. The misfolded proteins accumulate, creating clumps that are toxic to surrounding tissue.

Characterized by long incubation periods, these diseases cause spongiform changes in the brain and are associated with neuronal loss and a failure to induce inflammatory response.

In humans, the investigators explained, mutations in different regions of the PrP are associated with infectious neurodegenerative diseases with “remarkably” different clinical signs and neuropathological lesions. To explore the basis of this phenomenon, the investigators said, they made a CJD mouse that was exactly analogous to a previous knock-in model of a different prion disease, that is, FFI. Including the wild-type (WT) parent, they then had an allelic series of three lines, each expressing the same protein with a single amino acid difference, and with all native genetic regulatory elements intact.

To generate the models, Dr. Jackson and his colleagues created two mutated versions of the PrP-coding gene by changing a single codon. One mutation is known to cause FFI, while the other induces CJD. Unlike previous models that randomly inserted the mutations into the genome, occasionally increasing PrP expression, Jackson’s models faithfully mimic the human disease—from disease onset, to PrP production, to infectiousness. In the brain, his FFI mice develop neuronal loss in the thalamus, and his CJD mice experience spongiosis in the hippocampus and the cerebellum, reflecting the damage seen in the brains of human patients.

The FFI mice, the investigators said, developed neuronal loss and intense reactive gliosis in the thalamus, as seen in humans with the disease. In contrast, CJD mice had the hallmark features of CJD, including spongiosis and proteinase K-resistant PrP aggregates, initially developing in the hippocampus and cerebellum but absent from the thalamus.

The investigators concluded conclude that the diseases occurred spontaneously. Importantly, they said, both models created agents that caused a transmissible neurodegenerative disease in WT mice. Based on their observations, they concluded that single codon differences in a single gene in an otherwise normal genome can cause remarkably different neurodegenerative diseases and are sufficient to create distinct protein-based infectious elements.

Their work, they say, establishes that spontaneous mutations in the endogenous PrP gene can readily produce not only disease, but also infectious agents.

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