Featured Research

from universities, journals, and other organizations

Protein Misfolding, Not Mutant Gene, Key To Lethal Sleep Disorder

Date:
May 27, 1999
Source:
University Of Chicago Medical Center
Summary:
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 27th 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).

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 27th 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).

Related Articles


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, 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, M.D., Ph.D., 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, M.D., a professor of neurology, biochemistry and biophysics at U.C. 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, Ph.D., previously an assistant adjunct professor of neurology at UCSF, Dong Han, M.S., a postgraduate researcher in Prusiner's laboratory, and Stephen DeArmond, Ph.D., a professor of pathology and neurology at UCSF.


Story Source:

The above story is based on materials provided by University Of Chicago Medical Center. Note: Materials may be edited for content and length.


Cite This Page:

University Of Chicago Medical Center. "Protein Misfolding, Not Mutant Gene, Key To Lethal Sleep Disorder." ScienceDaily. ScienceDaily, 27 May 1999. <www.sciencedaily.com/releases/1999/05/990527043843.htm>.
University Of Chicago Medical Center. (1999, May 27). Protein Misfolding, Not Mutant Gene, Key To Lethal Sleep Disorder. ScienceDaily. Retrieved January 29, 2015 from www.sciencedaily.com/releases/1999/05/990527043843.htm
University Of Chicago Medical Center. "Protein Misfolding, Not Mutant Gene, Key To Lethal Sleep Disorder." ScienceDaily. www.sciencedaily.com/releases/1999/05/990527043843.htm (accessed January 29, 2015).

Share This


More From ScienceDaily



More Mind & Brain News

Thursday, January 29, 2015

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Signs You Might Be The Passive Aggressive Friend

Signs You Might Be The Passive Aggressive Friend

BuzzFeed (Jan. 28, 2015) "No, I&apos;m not mad. Why, are you mad?" Video provided by BuzzFeed
Powered by NewsLook.com
City Divided: A Look at Model Schools in the TDSB

City Divided: A Look at Model Schools in the TDSB

The Toronto Star (Jan. 27, 2015) Model schools are rethinking how they engage with the community to help enhance the lives of the students and their parents. Video provided by The Toronto Star
Powered by NewsLook.com
Man Saves Pennies For 65 Years

Man Saves Pennies For 65 Years

Rooftop Comedy (Jan. 26, 2015) A man in Texas saved every penny he found for 65 years, and this week he finally cashed them in. Bank tellers at Prosperity Bank in Slaton, Texas were shocked when Ira Keys arrived at their bank with over 500 pounds of loose pennies stored in coffee cans. After more than an hour of sorting and counting, it turned out the 81 year-old was in possession of 81,600 pennies, or $816. And he&apos;s got more at home! Video provided by Rooftop Comedy
Powered by NewsLook.com
How Technology Is Ruining Snow Days For Students

How Technology Is Ruining Snow Days For Students

Newsy (Jan. 25, 2015) More schools are using online classes to keep from losing time to snow days, but it only works if students have Internet access at home. Video provided by Newsy
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:

Breaking News:

Strange & Offbeat Stories


Health & Medicine

Mind & Brain

Living & Well

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile: iPhone Android Web
Follow: Facebook Twitter Google+
Subscribe: RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins