State researchers make inroads on prion study
Briana Wipf, bwipf@greatfallstribune.com 10:06 p.m. MST November 17,
2014
Sonia Vallabh and Eric Minkel have dedicated their careers to prion
research after Vallabh tested positive for a genetic mutation that will cause
her to develop fatal familial insomnia. (Photo: Aditi Mehta photo )
An illness that strikes family members in the 50s, affecting their behavior
and keeping them from sleeping. A shaking sickness that strikes only a tribe of
New Guinea. A disease that strikes sheep and goats, causing them to scrape their
bodies against anything they can get near, in an attempt to scratch an itch that
exists only in their brains.
Mysterious illnesses baffled doctors and scientists for years, until the
early 1980s when their cause was finally discovered. The discovery — that these
and other diseases are caused not by genetic mutations or outside pathogens like
viruses or bacteria, but by naturally occurring but damaged proteins within the
body — turned the scientific community on its head.
They are called prions — misfolded proteins that are infectious and cause
fatal neurodegenerative diseases in animals and humans.
And while they are unusual and glamorous, in a biological way, research
into prion disease is happening everywhere, including Montana, and livestock and
wildlife experts are keeping close eyes on populations to keep them
healthy.
Nose to the ground
Rocky Mountain Laboratories in Hamilton is a biomedical research facility
equipped for scientists to study some of the most dangerous, infectious diseases
on the planet.
In August, the New England Journal of Medicine published a paper that
represents a significant step forward in prion disease research. One of the
authors of the paper, which details a new test for Creutzfeldt-Jakob disease, is
Byron Caughey of RML.
Caughey has been working for 30 years on prion disease, and he admits his
fascination with the tiny, nearly indestructible rogue proteins is party
practical, partly because of simple fascination.
"We need to figure out how to cope with them," Caughey said. "That's the
bottom line, really, besides the scientific fascination with working with a
strange new class of infectious agents that is neither a virus nor a bacterium
nor a protozoan. So (there is) fundamental interest in prions as well as the
practical concerns of helping people and animals that get these diseases."
Creutzfeldt-Jakob disease, or CJD, is one of the more common prion
diseases. "Common" in this case is relative: CJD occurs in about one per one
million people, meaning about 300 Americans are diagnosed with CJD each
year.
The disease causes loss of muscular coordination, personality changes,
depression and insomnia, among other symptoms.
The traditional test for CJD lacked sensitivity and practicality, so the
team Caughey worked with developed a test that detects the biomarker of CJD
using nasal brushings. The test is more accurate and less invasive than other
methods.
It's a victory for Caughey and the rest of his team because being able to
identify the disease quickly may help with treatment, even if it doesn't exist
yet.
"One of the problems when people show up in the clinic with early
neurological signs is to get a definitive diagnosis, so these tests might really
help in that regard, and if therapies are available, to get them started as soon
as possible," Caughey said.
Caughey has worked on another prion disease, chronic wasting disease, that
affects deer, elk and moose.
While CWD has been detected in states and provinces surrounding Montana, to
date the only CWD-positive animals detected in the state were part of a game
farm near Philipsburg in 1999. Those animals were destroyed, according to the
Montana Fish, Wildlife and Parks website.
But FWP conducts a surveillance program that involves testing the carcasses
of sick or symptomatic animals. Beginning this year, live animals will be
collared and tested using a rectal biopsy in northern Montana, explained Dr.
Jennifer Ramsey, a wildlife veterinarian with FWP. This is the first time live
animals can be tested.
Of the animals that can get CWD, a highly infectious and fatal illness,
Ramsey said that it's thought it will turn up in deer first.
"I guess I'm a little bit surprised (it's never been detected in Montana),"
Ramsey said. "I think most people who work with wildlife think it's probably
going to show up eventually. We're kind of surrounded by it now."
The new surveillance program, which will provide data about how deer move
and interact among herds, may provide information about the spread of CWD among
infected and noninfected herds.
Ramsey said the public can help by reporting sick animals to FWP. Animals
that are thin, salivating, hanging their heads and drooping their ears should be
reported.
Two other prion diseases that affect animals, scrapie in sheep and goats
and bovine spongiform encephalopathy in cattle, are monitored by the United
States Department of Agriculture. BSE, commonly known as mad cow disease, is
rarely seen in the United States, with the last reported case in 2012. Scrapie
crops up in flocks occasionally, with the last reported case in Montana in April
2011.
Scrapie cases have decreased thanks to aggressive surveillance, testing and
certification of scrapie-free herds, according to the USDA-Animal and Plant
Health Inspection Services.
'It was essentially heresy'
McLaughlin Research Institute has become a biomedical outpost of the
Montana prairie. Inside its blue and orange exterior, MRI scientists have built
reputations studying neurodegenerative brain diseases like Alzheimer's,
Parkinson's and multiple sclerosis.
Institute director George Carlson focuses his research on Alzheimer's
disease, the brain-ravaging, progressive illness that eventually robs its
sufferers of their memory and ability to communicate.
Finding a way to test for and effectively treat Alzheimer's, costly both in
terms of monetary value and emotional toll on patients and families, is at the
top of the priority list for many.
Carlson believes Alzheimer's is a prion disease.
Carlson's career of prion research began in 1983, a year after the
publication of a monumental paper by Dr. Stanley Prusiner and his team.
Prusiner's paper argued that diseases like kuru and scrapie were caused not by a
slow virus, but by protein that occurred naturally within all people's
bodies.
"It was essentially heresy," Carlson said of Prusiner's theory.
Carlson was invited to join Prusiner's research group, but he wasn't
completely sold on the prion idea at first. But he said he found it "very
interesting."
As a graduate student, Carlson had done work on immune response. He had
come across papers about kuru, for example, that was attributed to a slow virus
but showed no symptoms of being caused by one. There is no fever, for example,
which would indicate an immune response. Carlson knew something wasn't quite
right with the slow virus theory, so when he was invited to work on Prusiner's
prion theory, he joined on.
But in those early days, many in the scientific community were skeptical of
or completely rejected Prusiner's theory. Up until then, infectious diseases
were thought to be caused by outside agents — a virus, bacterium or fungus, for
example. The idea that the infectious agent was coming from within the body flew
in the face of accepted scientific gospel.
"You go to meetings and people would accuse us of fraud," Carlson
recalled.
Three decades later, Carlson is still fascinated by the prion, but he's
turned his attention to neurodegenerative diseases, particularly Alzheimer's
disease.
Like Carlson, Dr. Deborah Cabin applies what science has learned about the
prion to her research on Parkinson's disease and a protein called
alpha-synuclein, which misfolds in patients who have that disease.
Likewise, the proteins amyloid-beta-peptide and tau misfold in Alzheimer's
disease, causing the plaques and tangles in the brain that are the disease's
hallmark.
Everyone has alpha-beta-peptide, which makes it such a challenge for
scientists to understand where the trouble comes in.
Alpha-synuclein, Cabin's protein, also is naturally occurring. In
Parkinson's patients, it seems to occur in higher numbers. So, it would make
sense to remove the alpha-synuclein or prevent the body from producing it, to
cure or prevent the Parkinson's disease, right?
But Cabin has tried that, and it isn't so simple. Mice that lack
alpha-synuclein end up living shorter lives than control mice, indicating the
protein may play a role in the aging process. But that's only a hypothesis at
this point, and another wrench in the prion mystery.
But Cabin, like many researchers, is motivated by the unknown, by the
questions she still needs to answer.
"If we knew the outcome of a test, there's no reason to do it," she
said.
A test she once ran on mutagenic mice, one that took years and thousands of
mice to complete, did not give her satisfactory results because, she says, she
did not choose the right assays for the test.
"I still want to find out. This is the sort of thing I lie in bed at night
and think about," she said.
With their rarity, it may be easy to lose sight of the fact that prion
diseases affect real people.
One hereditary prion disease, fatal familial insomnia, unexpectedly became
part of the lives of Sonia Vallabh and Eric Minikel in 2011.
Vallabh's mother was born with a spontaneous genetic mutation that
guaranteed she would get FFI. After her mother's death, Vallabh was tested and
discovered that she, too, will contract FFI someday, perhaps when she is in her
50s.
Three years later, the married couple has devoted their lives to raising
money and finding a cure for prion disease. They have also left their original
careers — Vallabh was trained as a lawyer and Minikel had a city planning and
software engineering background — to pursue PhDs in biological and biomedical
studies at Harvard University.
Vallabh and Minikel are also working with McLaughlin Research Institute in
Great Falls. MRI director Dr. George Carlson is doing experiments with a new
drug candidate on a colony of mice with FFI.
"Obviously, treating the mice is a first step, and that doesn't mean you
can treat the people, but in prion disease, we couldn't even treat the mice for
decades," Minikel said.
The two have started a nonprofit called the Prion Alliance
(www.prionalliance.org) to raise awareness of prion diseases and money for
research. Minikel also maintains a blog, www.cureffi.org.
Even with the specter of contracting FFI, an illness that causes
personality changes and prevents patients from sleeping, Vallabh remains
upbeat.
"I'm so grateful we decided to get the (genetic) test results," said
Vallabh, 30. "Once we knew, we knew, and it could start becoming another thing
that we knew about our life."
Looking ahead
As research has progressed, the term "prion" is almost taking on a new
meaning, a class of proteins, Cabin said.
"Mechanistically, they're similar but with misfolding of different
proteins," Carlson said.
Caughey believes the nasal brushings test he and his research partners
devised may be adaptable for early tests for not only Alzheimer's and
Parkinson's but also Huntington's disease and amyotrophic lateral sclerosis, or
Lou Gehrig's disease.
"(These diseases) all involve accumulation of abnormal clusters of
different proteins and it's possible, we hope it's possible, that we could get
earlier, more definitive diagnoses of these diseases as well as by developing
related types of amplification tests," he said.
With research into this class of diseases ongoing, scientists continue to
make advances and learn more about how prions work and cause disease. And while
the pace may at times seem painstakingly slow, breakthroughs may be around the
corner.
"Sometimes it's like plodding, but then with this diagnostics test, for
instance, we've made very rapid and exciting (progress)," Caughey said. "Who
knows, maybe tomorrow we'll make a big discovery in the direction of
therapeutics."
Self-Propagative Replication of Ab Oligomers Suggests Potential Transmissibility in Alzheimer Disease
Received July 24, 2014; Accepted September 16, 2014; Published November 3, 2014
http://www.plosone.org/article/fetchObject.action?uri=info%3Adoi%2F10.1371%2Fjournal.pone.0111492&representation=PDF
Received July 24, 2014; Accepted September 16, 2014; Published November 3, 2014
http://www.plosone.org/article/fetchObject.action?uri=info%3Adoi%2F10.1371%2Fjournal.pone.0111492&representation=PDF
Monday, November 3, 2014
USA CJD TSE PRION UNIT, TEXAS, SURVEILLANCE UPDATE NOVEMBER 2014
National Prion Disease Pathology Surveillance Center Cases Examined1
(October 7, 2014)
***6 Includes 11 cases in which the diagnosis is pending, and 19
inconclusive cases;
***7 Includes 12 (11 from 2014) cases with type determination pending in
which the diagnosis of vCJD has been excluded.
***The sporadic cases include 2660 cases of sporadic Creutzfeldt-Jakob
disease (sCJD),
***50 cases of Variably Protease-Sensitive Prionopathy (VPSPr)
***and 21 cases of sporadic Fatal Insomnia (sFI).
Friday, January 10, 2014
vpspr, sgss, sffi, TSE, an iatrogenic by-product of gss, ffi, familial type
prion disease, what it ???
Tuesday, November 04, 2014
The pathological and molecular but not clinical phenotypes are maintained
after second passage of experimental atypical bovine spongiform encephalopathy
in cattle
Tuesday, November 04, 2014
Six-year follow-up of a point-source exposure to CWD contaminated venison
in an Upstate New York community: risk behaviours and health outcomes 2005–2011
MOM DOD 12/14/97 confirm ‘hvCJD’ just made a promise to mom, NEVER FORGET!
and never let them forget. ...
Terry S. Singeltary Sr.
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