Protein misfolding, not mutant gene, key to lethal sleep disorder

May 26, 1999

When Shakespeare wanted the witches in "Macbeth" to utter a truly horrible curse, he had them deny their victim sleep. Now, almost 400 years later, in the May 27, 1999 issue of the New England Journal of Medicine, medical researchers from the University of San Francisco and the University of Chicago describe the first case of the neurologic disorder that matches the curse: sporadic fatal insomnia (SFI).

The symptoms and neuropathology of SFI are identical to an inherited disorder described by Italian scientists in 1986, called fatal familial insomnia (FFI). FFI is triggered by a tiny mutation in a particular gene that prompts the protein made by that gene to fold into an abnormal shape like a deformed origami.

The misfolded protein--called a prion--not only doesn't function, but it also cannot be chewed up by enzymes or eliminated from the brain, so it gradually accumulates, causing untreatable sleeplessness, loss of coordination, loss of mental function, and death--usually within less than two years.

But SFI, the non-inherited version, occurs without the abnormal gene.

"We found a disease that is indistinguishable from the genetic disorder but lacks the disease gene," said Jim Mastrianni, MD, PhD, assistant professor of neurology at the University of Chicago and lead author of the study. "Sporadic fatal insomnia is an exact phenocopy, but not a genocopy of fatal familial insomnia."

The researchers, led by Nobel laureate Stanley Prusiner, MD, a professor of neurology, biochemistry, and biophysics at the University of California at San Francisco, also demonstrate that the sporadic disorder can be transmitted to transgenic animals that have normal copies of the human gene that is mutated in FFI. This indicates that the specific manifestations of the disease are determined not by the abnormal gene or the sequence of amino acids in the protein, but purely by the abnormal shape taken on by the protein.

This supports the controversial notion, says Mastrianni, that "even in the familial form, it's the prion strain, the precise conformation of the misfolded protein, and not the variation in the gene that ultimately determines the consequences of the disease."

Familial fatal insomnia has been found in only 24 extended families worldwide, but the sporadic version, though still quite rare, may prove somewhat more common, accounting for "most or all cases of pure thalamic dementia," suggest the authors.

Perhaps best known as the cause of "mad cow disease" (bovine spongiform encephalopathy), prions can cause several uncommon human brain disorders--such as Creutzfeldt-Jakob disease, Gerstmann-Straussler-Scheinker disease, kuru and FFI--and may even be suspects in more common disorders such as Alzheimer's disease, ALS, or Parkinson's disease.

The different prion disorders all result from gross irregularities in the folding of a particular protein--the normal function of which is not known. The initial folding error may be induced by a genetic mutation or may occur spontaneously. It then spreads via protein-to-protein contact, with the misshapen version somehow inducing normal proteins to take on the new, indigestible structure.

The first SFI patient was a previously healthy 44-year-old California man who developed increasing trouble falling asleep. His personal physician initially dismissed his complaints, saying they were "all in his head;" but after about four months of sleeping an average of one hour per night the patient began to have trouble walking, lost weight, and produced tears excessively (consistent with the witches' curse to "dwindle, peak, and pine").

The patient was referred to Dr. Mastrianni (at that time, a clinical instructor of neurology and medical director of Alzheimer's diagnostics at UCSF), who began the testing that led to the diagnosis. Large doses of hypnotic drugs were only briefly beneficial, and the patient suffered gradual but progressive loss of coordination and short-term memory and increasing difficulty separating dreams from reality. One year after the onset of symptoms he was admitted to a long-term care facility. Four months later, severely delusional, he died.

At autopsy, the patient's brain showed damage that was entirely consistent with FFI but no evidence of the abnormal gene in any tissue. A search found no family member with a similar disease. The researchers then used extracts from the patient's brain and from the brain of a different patient with confirmed FFI to transmit the disorder to transgenic mice with a mouse/human prion protein gene. The neuropathology in the affected mice was indistinguishable, indicating that these strains were identical.

Other members of the research team were Randall Nixon; Robert Layzer; Glenn Telling, PhD, previously an assistant adjunct professor of neurology at UCSF; Dong Han, a postgraduate researcher in Prusiner's laboratory; and Stephen DeArmond, PhD, a professor of pathology and neurology at UCSF.

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