Pass the prion: Inherited mutation leads to spontaneous prion infectivity

A new study with transgenic mice provides the first concrete evidence that a disease-associated prion protein mutation in an otherwise normal mammalian brain can generate a unique self-perpetuating transmissible agent that is infectious to other animals. In addition to revealing critical new insight into prion biology, the research, published by Cell Press in the August 27 issue of the journal Neuron, introduces a valuable mouse model of a type of inherited human prion disease associated with deadly insomnia.

Prion diseases are a varied group of infectious progressive fatal neurodegenerative disorders in wild and domestic animals (chronic wasting disease, scrapie, and mad cow disease) as well as humans (Creutzfeldt-Jakob disease and fatal familial insomnia, FFI). Although the clinical symptoms vary between the different prion diseases, loss of brain tissue is common to all. Prion proteins (PrPs), which are common throughout the central nervous system, are deformed in prion diseases and clump up, interfering with normal function.

"The prion hypothesis holds that misfolded PrPs are the basis of infectivity and that PrP mutations associated with inherited prion diseases in humans are all that is needed to produce these infectious units spontaneously," explains senior study author Dr. Susan Lindquist from the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts. "However, the crucial prediction that a disease-associated PrP mutation can, in fact, generate a prion that can transmit disease to a normal mouse had never been experimentally demonstrated."

Walker Jackson, a postdoctoral fellow in the Lindquist lab, replaced the endogenous PrP gene with one carrying the mouse equivalent of a human mutation associated with a unique form of inherited prion disease, FFI. The researchers chose this particular mutation because FFI has symptoms and neuropathology that are distinct from other prion diseases, such as disruption of the autonomic nervous system, insomnia and a specific loss of neurons in a part of the brain called the thalamus.

"We hoped that the pathology associated with the FFI mutation would be both sufficiently reminiscent of the pathology of human FFI and, most importantly, sufficiently distinct from the pathology of other mouse prion models to ensure that disease was due to the FFI-mutated PrP protein," offers Dr. Jackson.

The mice with the FFI mutation exhibited biochemical, physiological, behavioral and neuropathological abnormalities remarkably similar to human FFI and different from mice expressing other PrP mutations. The researchers then injected a small amount of brain tissue from the FFI mice into mice expressing physiological amounts of PrP and found that the unique pathology was transmitted to the normal mice. The authors were careful to confirm that transmissible infection required expression of PrP and did not arise from previous exposure to contaminating agents.

The results show that the FFI PrP mutation was sufficient to induce a unique neurodegenerative disease and the spontaneous generation of prion infectivity. "Our work fulfills a long standing and long unfulfilled prediction of the prion hypothesis. In the context of an otherwise normal animal, simply changing a single codon in the PrP sequence is sufficient to cause spontaneous appearance of a transmissible agent for neurodegeneration," concludes Dr. Lindquist. "We greatly hope these mice will be an important resource in studies to uncover the mechanisms of action of FFI and for test trials of potential treatments for this dreaded disease," adds Dr. Jackson.

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The researchers include Walker S. Jackson, Whitehead Institute for Biomedical Research, Cambridge, MA; Andrew W. Borkowski, Whitehead Institute for Biomedical Research, Cambridge, MA, Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA; Henryk Faas, Massachusetts Institute of Technology, Cambridge, MA; Andrew D. Steele, Whitehead Institute for Biomedical Research, Cambridge, MA; Oliver D. King, Whitehead Institute for Biomedical Research, Cambridge, MA; Nicki Watson, Whitehead Institute for Biomedical Research, Cambridge, MA; Alan Jasanoff, Massachusetts Institute of Technology, Cambridge, MA; and Susan Lindquist, Whitehead Institute for Biomedical Research, Cambridge, MA, Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA.