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9/13/2015 Helsingin Sanomat 2006

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Helsingin Sanomat 2006

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Deadly Peptides

Horror Show

Displays:

The polypeptides which, if not folding,

killing even a cow!



Marc Baumann

University of Helsinki

Medical Faculty

Biomedicum Helsinki

Phone: 0919125200 / Fax: 0919125206

email: [email protected]

http://research.med.helsinki.fi/corefacilities/proteinchem

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Australia / Papua New Guinea in 1950

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mailto:[email protected]

https://translate.google.com/translate?hl=tr&prev=_t&sl=fi&tl=en&u=http://research.med.helsinki.fi/corefacilities/proteinchem



Vincent Zigas

Carleton Gajdusek

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KURU patient

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KURU patients (children and women?)

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The brain is almost gone

KURU brain



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Viruses are small packages of genetic material that

can reproduce only inside the cell

The virus theory

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infectious disease rehabilitation

foreign

substance

quantity

in the body



Dates

Note: The time required for the emergence of the disease does not really add up KURU disease ...

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foreign matter antibody

identification

identification

identification

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Antibody production in mice does not succeed



Note: KURU patients do not have antiinflammatory and fever ...

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Sheep's story

Dr. Bill Hadlow contact ...

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Scrapie in sheep suffering from the disease

(to scrape ...)

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Hadlow find out that:

Sheep brain

similar to

confusingly KURU

of patients

brains!



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In the meantime, Americans

suddenly find that:

KURU patient

brain material

Transfer monkeys

leads monkey

sudden

death ... ???

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Human > monkey

sheep > lamb



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Back to the future I

Let's for a moment

Germany

Beginning of the 1900s ...

Germany 1900 / Breslau

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Here, working

Dr. Creutzfeldt



Germany 1900 / Breslau

Alois Alzheimer's

passing the booth

when ...

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23yearold Bertha Elschker

is brought to the hospital Alois

Alzheimer's, led by department

Hans Gerhard Creutzfeldt in which

working ...

What Bertha sick ??

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Bertha's brains resemble

confusingly later

discoverable KURU patient

brains!

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1913 Dr. Creutzfeldt

reported a new disease

which is named

CreutzfeldtJakob disease



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Back to the Future II

The Americans take the opportunity to explore both

even though such diseases. Gadjusek does not believe that diseases

adhere to each other in any way ...

(Cadjusek makes a mistake ...)

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Stanley Prusiner presents itself ...



Stanley B. Prusiner

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Stanley Prusiner does not believe Cadjusek'iä

but take sooloilemaan ...

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The cause of the disease can be isolated biochemical

methods (Stanley Prusiner)



Gel filtration method

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KURU and CJD patient's brain found strange

threads

(electron microscopic image)

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Structure The study reveals the change in the shape of Prion protein



Deadly

shape

Usual

shape

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Prion protein is present in almost

and nearly every cell

Each Object



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Prion diseases caused by a protein known as other

KURU is only one shape among

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Why pathogenesis of the disease is so special?



Prions are simple proteins, which are much smaller

as the smallest viruses. Prions contain no genetic material.

All other hitherto known for causing infectious diseases, substance

contain genetic material.

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Prions are not like parasites, namely parasites living in their host,

often resulting in longterm parasitic.

STILL prions present a very longterm diseases ...

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Prions are also not the bacteria that protects the often strong

the wall so that they can remain free isännästään a long time.

STILL prions remain for many years ...

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A deadly form of prion spread in animals and humans

All known prion diseases are

deadly. Since the body's defense mechanism

does not recognize them as foreign, they will not be

antibodies. Sheep Scrapie disease

was discovered in the 1800's.

It has since spread to other animals

such as minkkiin, cats and cows,

through contaminated food.

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Symptoms of prion disease may be quite different shapes!



Scrapie in sheep suffering from the disease scratches himself ...

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Prion protein can cause the disease itself, or hereditary

in the form of the genetic change.

New Guinea, the natives spread Kuru disease while eating

each other's brains (cannibalism).

CreutzfeldtJakob disease (CJD) often develops by itself, but the 10

15% of the CJD disease due to inherited prion protein gene defect.

CJD sister disease, a deadly nukkumistauti (fatal familial insomnia

(FFI), Gerstmann or SträusslerScheinker disease (GSS), are always

perinöllisiä.

The new variant form of CJD is a type of spread 150 of the patient, the spreading of contaminated.

through the cow meat (mad cow disease in humans).

Human prion diseases



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Different destroy prions in various parts of the brain

Prions destroy brain. The spongy shape is achieved when the nerve cells die.

The impact of the disease depend on which part of the brain is destroyed.

Cerebral cortex When this part is destroyed,

the patient loses his memory and mental level,

sometimes also in vision deteriorates (CJD).

Thalamus destruction of this part of the cause

deadly nukkumistaudin (FFI).

Cerebellum destruction in this section

cause a failure of muscle control.

(Kuru, GSS).

Brain stem spread to this part of the prion

cause mad cow disease. (BSE).

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Genetic mutations that cause differences in forms of the prion protein

when it is spread in different parts of the brain. Perinöllisessä



nukkumistaudissa (familial insomnia (FFI), mutoitunut prion

(purple squares) collects thalamus. As a result, the patient can not

no longer sleep. CreutzfeldtJakob's disease, prion protein accumulates in

mainly cerebraalisen cortex area (the red dots and regions).

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Dr. Jekyllista Dr. Hydeksi

Prionproteiini can adopt two different threedimensional structure.

Normal form (PrPC) can be deformed deadly

(PrPSc) form. The change causes a chain reaction whereby

an increasing number of PrPC turns into PrPSc muotoon.Kun PrPSc protein

has formed enough to start protein säikeistyä. These threads

tuohoavat nerve cells. PrPSc is extremely durable. It will not be destroyed

even at high temperatures, no radiation or harsh chemicals.

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Prion diseases may be transmitted to three different

1. Horizontal transmission eg. Sheep

cow (BSE).

2. Perinöllisesti, mutations in the prion protein

transfer the disease from an older child.

3. The disease can occur spontaneously.



4. The disease can move iatrogenic

The spread of BSE infectivity disease

When a cow eats fodder which is made of sheep

parts of the carcase, prions are transferred from the rumen

nerve cells from where they are transported to the brain.

Here prions accumulate and change

the normal prion protein sick

PrPSc. Years later, BSE created

when enough of the wrong format was born.

Nerve cells die and the death of the cow begins.

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Iatrogenic transmission

Brain tissue example ....

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Kuru epidemic started long ago and has decreased since 1950.

The epidemic of mad cow disease began in 1985 when approx. 170 000 cows had fallen ill.



Kuru disease Mad cow disease

This image shows how the disease disappeared

among the natives when they stopped

kannibalisimin. In children, the disease disappeared

faster than adults.

Sairastumisaika the disease is up to 30 years.

This picture shows the BSE epidemic

the spread. It reached a maximum

its value in 1992 when 37,000 animals became ill

the same year. When the feed was discontinued,

The occurrence of BSE decreased considerably.

How long will people get sick?

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What happens with

the prion?

==> Not much



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Celebrated a moment in history ...

And is considered the prion is really about?

Back to the Future III

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Germany 1900

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Alois Alzheimer's disease

What did Alois Alzheimer?

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Amyloid deposits comprise threads

(electron microscopic image)

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APP

The strands consist of only a small part of the protein

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A good form of Alzheimer's protein



A deadly form of Alzheimer's protein

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Structure The study reveals the change in the form of Alzheimer's protein

Deadly

shape

Usual

shape



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Why such proteins

kill ???

"Glue" theory

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Alzheimer's disease, research has shown that ...



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Good shape deadly form

All AD genetic

Risk factors cause

incorrect folding

reproduction.

SDSPAGE Binding Assay

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How wrong folding

due to ???



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Alzheimer's amyloid precursor protein

sA β

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Critical amino acids



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Critical amino acids physicochemical properties:

Alzheimer's Amyloid



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Prion protein amino acids critical area

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Is this enough?



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Prion hypothesis proven?

Spongiform Diseases:

Waiting for the Final Experiment

Science, Dec 16, 2005

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Fishing Säikeistyvien proteins

will be critical amino acids and search for

a computer in the protein data banks



similar amino acids other

proteins

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... .MSSY AFFV QT ....

... .HQKL VFFA ED ....

Random database search ...

Amphoterin

Alzheimer's Amyloid

Baumann et al (2000) Biochem. J. 349: 7784

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Critical amino acids physicoCHEMICAL properties:

Amphoteriini



Baumann et al (2000) Biochem. J. 349: 7784

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GKGDPKKPRGKMSSY AFFV QTCREEHKKKH

PDASVNFSEFSKKCSERWKTMSAKEKGKFE

DMAKADKARYEREMKTYIPPKGETKKKFKD

PNAPKRPPSAFFLFCSEYRPKIKGEHPGLS

IGDVAKKLGEMWNNTAADDKQPYEKKAAKL

KEKYEKDIAAYRAKGKPDAAKKGVVKAEKS

KKKKEEEDDEEDEEDEEEEEEEEDEDEEED

DDDE

Amphoteriinin sequence

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GKGDPKKPRGKMSSY AFFV QTCREEHKKKH

PDASVNFSEFSKKCSERWKTMSAKEKGKFE

DMAKADKARYEREMKTYIPPKGETKKKFKD

PNAPKRPPSAFFLFCSEYRPKIKGEHPGLS

IGDVAKKLGEMWNNTAADDKQPYEKKAAKL

KEKYEKDIAAYRAKGKPDAAKKGVVKAEKS

KKKKEEEDDEEDEEDEEEEEEEEDEDEEED

DDDE

EndoLys EndoLys

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Formed Amphoteriinin Thread



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ApoE

Amphoteriini

and apoE

togetherSDSPAGE Binding Assay

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ApoE

Amphoteriini

and apoE

togetherSDSPAGE Binding Assay



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Can we predict who will do

amyloid and säikeistyy ??

Chou and Fasman ....

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1.1

1.3

1.5

Alphahelix

Betasheet Betasheet

Secondary structure prediction



0.5

0.7

0.9

MSSYAFFVQTC

0.6

0.8

1

1.2

1.4

SNNFGAILSS

NGNCFILD

HQKLVFFAE

Betaturn

Betaturn

Betasheet

Alphahelix

Alphahelix

BetaturnAmphoterin fragment

Islet amyloid fragment Alzheimer's amyloid fragment

Betasheet

Alphahelix

Betaturn

Gelsolin fragmentProteinx

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In Conclusion

Amyloids are quite naturally occuring

risk factors for the life ...

Which the nature can just sometimes

not deal with.

They form Spontaneously by mutations

Which are only controlled by the evolution.

BAD LUCK ... or ???

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So we are dealing with just an ordinary and quite

with the general case. In nature, there are many

prionlike proteins. All

they way interfere with the body's activities,

some more than others. The worst killing

fast, nonhazardous slower.

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The Yeast story ...

Yeast uses a prionlike protein to control for its life

in various environmental conditions.

It keeps this protein in an amyloidlike form if it is not

needed ...

When needed, it can produce the same protein in a

soluble form.



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Will this story here ???

?

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BREAKING NEWS

Reuters: Mad cow disease in Croatia

From Correspondents in Zagreb, February 17, 2006

CROATIA today said it had detected bovine spongiform

encephalopathy (BSE) in a dead heifer (cow), in the country's

first case of mad cow disease.

18 Feb 2006



No More Additional Cases of Mad Cow Disease in Canada

23 Feb 2006

New mad cow case to reported in Poland

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What About Other Animal TSE's?

One case of BSE in the US

TSE's has been found in the United States:

Scrapie in sheep and goats, transmissible mink

encephalopathy, and chronic wasting disease of deer and

elk.

Elk are deer and mink mink ???

Mink are feeding the BSE feed and

is released exactly where moose are !!!

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Prion protein amino acids critical area

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Not so bad that something

silver lining ...

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SCIENCE, 3/2007

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Amyloids always occur

two forms.



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Amyloidogenic

proteins

Pathogenic

form

Nonpathogenic

form

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Amyloidogenic

conformation

Nonamyloidogenic

conformation



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DAEFRHDSGYEVHHQK LVFFA EDVGSNKGAIIGLMVGVVIA

1 42

A β 142

N C APPA β1 695

Sequences of Alzheimer's β sheet breaker peptides

iA β 11 RDLPFFPVPID

iA β 9 RDLPFFPVD

iA β 7 LPFFPVD

iA β 6 LPFFVD

iA β 4 LPFF

iA β 3 PFF

iA β 5 LPFFD

β sheet breaker peptides

Soto and Baumann (1996) Biochem. Biophys. Res.Commun. 226: 672680

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Activity of a β sheet breaker peptide

In vitro activity Activity in cells



Activity in the rat model

TreatmentControl

TreatmentControl

TreatmentControl

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Some amino acid polymorphisms in the PrP of human, sheep,

and mouse appear to Influence the onset and phenotype of

prion disease

Notably, position 166 (129 in human) is polymorphic

for the Met or Val in human PrP and modulates protease

sensitivity of PrPSc.

All cases of vCJD to date, the novel human variant caused by the

BSE prion strain from cattle, are Homozygous for Met166. However,

Heterozygosity is not a general protective feature.

Residues 127157 play a major role in the PrPC / PrPSc interface.

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Degree Susceptibility to scrapie can now be Established by molecular techniques



Scrapie is a fatal, degenerative disease affecting the central nervous system of sheep

and goats. It is one of the transmissible spongiform encephalopathies (TSEs). The

infectious agent is a prion That does not cause detectable immunitary or inflammatory

response. So no external signals are visible in the first step of the disease. Infected Flocks

can contain a high percentage of Susceptible animals. Animals sold from infected Flocks

can spread to other Scrapie Flocks.

Since no vaccine or therapeutic means are currently available, scrapie control programs

rely on is the selective breeding of scrapie resistance individuals.

Genetically, susceptibility to scrapie is largely controlled by three polymorphic amino

acid positions of the ovine prion protein gene and reliable genotyping of Corresponding

DNA polymorphism can be used as a basis for selection Decisions.

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GenotypeGroup NSP * Degree of resistance / susceptibility to scrapie

ARR / ARR Sheep That are Genetically resistant to scrapie

ARR / ahq Sheep That are Genetically resistant to scrapie, but will need

ARR / ARH careful selection when used for further breeding

ARR / ARQ

ARQ / ARH Sheep That Genetically have little resistance to scrapie and

ARQ / ahq will need careful selection when used for further breeding

Ahq / ahq

ARH / ARH

Ahq / ARH

ARQ / ARQ

ARR / VRQ Sheep That are Genetically Susceptible to scrapie and shouldnt

not be used for breeding Unless in the context of controlled

breeding program

Ahq / VRQ That Sheep are highly Susceptible to scrapie ans shouldnt

ARH / VRQ not be used for breeding

ARQ / VRQ



VRQ / VRQ

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