PrionDisease

Prion Disease: 

Prion Disease Mark F. Shinnick March 24, 2007

QUESTIONS:What key genetic difference characterizes Prions apart from all earlier-known forms of infection?Which of the two forms of Prions is regarded as infectious, and what effect does it play a role in producing in non-infectious Prions ?Is there a chemical difference between infectious, and non-infectious prions? In what tissue type do prions become concentrated? How is Prion infection most typically acquired?Since no “cure” is known, why is mere Prion infection still not a automatic death sentence?Name one type of species which is used to demonstrate Prion infection.Name a wild animal population that is experiencing a Prion infection epidemic.: 

QUESTIONS: What key genetic difference characterizes Prions apart from all earlier-known forms of infection? Which of the two forms of Prions is regarded as infectious, and what effect does it play a role in producing in non-infectious Prions ? Is there a chemical difference between infectious, and non-infectious prions? In what tissue type do prions become concentrated? How is Prion infection most typically acquired? Since no “cure” is known, why is mere Prion infection still not a automatic death sentence? Name one type of species which is used to demonstrate Prion infection. Name a wild animal population that is experiencing a Prion infection epidemic.

BULLET POINTS:Prions - a new biological principle of infection ….by a “mere” protein segment, not a whole genome!! All cases of “Prion disease” are fatal.2 types of prions exist: Pathogenic and non Pathogenic, both chemically the same. A physically “twisted” infectious Prion protein is somehow capable of effecting “twisting” of other prions and, after a short or very lengthy delay since infection, accumulations cause rapid and fatal disease states in the brains and nervous clusters of man and animals.The “twisted” or conformal-changed prion affects non-twisted Prions.Until prions were discovered, duplication of a infectious particle without a genome was considered impossible.We acquire infection by eating infected meat/nervous tissue. Infection does not automatically mean “disease”. A long possible latency for humans. Infection within some wild animal populations, like Elk and Deer, is rapidly spreading.Transgenic species, such as mice, have been created Prion-free. They can then be purposely infected with pathogenic prions for research.: 

BULLET POINTS: Prions - a new biological principle of infection ….by a “mere” protein segment, not a whole genome!! All cases of “Prion disease” are fatal. 2 types of prions exist: Pathogenic and non Pathogenic, both chemically the same. A physically “twisted” infectious Prion protein is somehow capable of effecting “twisting” of other prions and, after a short or very lengthy delay since infection, accumulations cause rapid and fatal disease states in the brains and nervous clusters of man and animals. The “twisted” or conformal-changed prion affects non-twisted Prions. Until prions were discovered, duplication of a infectious particle without a genome was considered impossible. We acquire infection by eating infected meat/nervous tissue. Infection does not automatically mean “disease”. A long possible latency for humans. Infection within some wild animal populations, like Elk and Deer, is rapidly spreading. Transgenic species, such as mice, have been created Prion-free. They can then be purposely infected with pathogenic prions for research.

Presentation of the Nobel Prize in Physiology or Medicine 1997:“This year's Nobel Prize in Physiology or Medicine has been awarded to Stanley B. Prusiner for his discovery of prions - a new biological principle of infection. … What is a Prion? It is a small infectious protein capable of causing fatal dementia-like diseases in man and animals.…Until prions were discovered, duplication without a genome was considered impossible. Stanley Prusiner,Your discovery of the prions has established a novel principle of infection and opened up a new and exciting area in medical research. On behalf of the Nobel Assembly at the Karolinska Institute I wish to convey to you my warmest congratulations and I now ask you to step forward to receive your Nobel Prize from the hands of His Majesty the King.”: 

Presentation of the Nobel Prize in Physiology or Medicine 1997: “This year's Nobel Prize in Physiology or Medicine has been awarded to Stanley B. Prusiner for his discovery of prions - a new biological principle of infection. … What is a Prion? It is a small infectious protein capable of causing fatal dementia-like diseases in man and animals. …Until prions were discovered, duplication without a genome was considered impossible. Stanley Prusiner, Your discovery of the prions has established a novel principle of infection and opened up a new and exciting area in medical research. On behalf of the Nobel Assembly at the Karolinska Institute I wish to convey to you my warmest congratulations and I now ask you to step forward to receive your Nobel Prize from the hands of His Majesty the King.”

Prions are small protein segments from membranes. There turns out to be at least two forms of Prion: one misshapened: PrPS, the other not: PrP. (The S represents the Prion for Scrapie)Non-infectious Prions undergo a “reconformation” , a “misfolding”…apparently after being influenced in a unknown way by their misshapened sisters. Chemically they appear the same! Infectous Prions migrate up the nerves and into the brain and heart. The accumulation of these abnormal prions in the central nervous system, the heart, or possibly other sites not yet discovered is what brings on disease.: 

Prions are small protein segments from membranes. There turns out to be at least two forms of Prion: one misshapened: PrPS, the other not: PrP. (The S represents the Prion for Scrapie) Non-infectious Prions undergo a “reconformation” , a “misfolding”…apparently after being influenced in a unknown way by their misshapened sisters. Chemically they appear the same! Infectous Prions migrate up the nerves and into the brain and heart. The accumulation of these abnormal prions in the central nervous system, the heart, or possibly other sites not yet discovered is what brings on disease.

Slide6: 

Prion Understanding Milestones 1966, Alper observed small target size of the infectious material to UV inactivation at 254 nm (Alper et al., 1966 ; Alper et al., 1967 In 1967, Griffith had suggested “reconformation” of proteins. In 1993, Weissman showed PrP-deficient mice were immune to Prion infection. Established PrP protein as essential component of the disease. “PrPC is a soluble protein, the PrPSc form is stubbornly insoluble” Jonathan S. Weissman

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Prion Understanding Milestones Similar Tissue levels of PrP mRNA were found in uninfected and Scrapie-infected tissues. So PrPSc Was not normally replicating.Prusiner, S.B. Science 216, 136-144 (1982). By 1985 the gene encoding the PrPSc Prion protein was found by various researchers to be expressed in all animals tested, humans too. Definition : Exon: The region of a gene that contains the code for producing protein. Each exon codes for a specific portion of the complete protein. Exons are separated by introns, long regions of DNA that have no apparent function. “PrP derives from a host protein encoded by a single-copy gene having three known exons in mice, cattle and sheep but only two exons in hamsters and humans.” IBR/CSI Center for Developmental Neuroscience and Developmental Disabilities, Staten Island, NY 10314, USA.

Slide8: 

The Scrapie agent is very small. Could not be affected by UV and is resistant to proteases… This got Prusiner’s attention. By 1981 He had purified the agent “100- to 1,000-fold with respect to protein”. Prusiner, S.B. et al., Proc. Natl. Acad. Sci. 78, 6675-6679 (1981) He termed the: Normal Prion protein : PrPC, Infectious form: PrPSc

The term Prion was coined by Stanley B. Prusiner 1982 for a "proteinaceous infectious particle that lacks nucleic acid”: 

He purified apparent cause for mad cow disease, Bovine Spongiform Encephalopathy: (BSE) -Infection route: eating contaminated bovine meat/nerve tissue. Such infection has some other animal variants: * Scrapie: sheep (18th century) (PrPS prion) * TME (transmissible mink encephalopathy): mink * CWD (chronic wasting disease): muledeer, elk (The incidence of chronic wasting disease with elk appears to be spreading rapidly.) THE UNDERSTANDING ABOUT PRION EFFECTS IN ANIMALS GROWS: IT’S A BRAND NEW FIELD. The term Prion was coined by Stanley B. Prusiner 1982 for a "proteinaceous infectious particle that lacks nucleic acid”

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Transmissible spongiform encephalopathies (TSEs) Reported Instances Distribution -Infection route: eating contaminated bovine meat/nerve tissue.

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Disinfection Prusiner found that: sodium dodecyl sulfate, phenol, urea, digestion with proteinase K and trypsin, and chemical modification with diethyl pyrocarbonate, deactivated these PrPSc proteins. Prusiner, S.B. Science 216, 136-144 (1982). Ozone was found by other scientists to work under specific conditions.

More recently, infectious prions found concentrated in hearts of transgenic mice. False color image of a mouse heart infected with Scrapie. : 

More recently, infectious prions found concentrated in hearts of transgenic mice. False color image of a mouse heart infected with Scrapie. “Prion-induced amyloid heart disease with high blood infectivity in transgenic mice,” (Science, 313:94-97 (2006) “Until now, Prion disease has been thought of as a chronic neurological condition,” says Scripps Research Professor Michael B. Oldstone 2006

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For Humans, diseases recently seen as Prion in origin are: *nv-CJD or v-CJD are caused by a strain very much like the BSE agent. Some people now call this disease Human BSE (2006) Work seeks to create immunity. * CJD: Creutzfeld-Jacob Disease (1920;s) 1 in 10,000 humans (likely more) infected with CJD at the time of death. Infection does not denote a disease state. Disease appears more prone after age 60. (http://www.tulane.edu/~dmsander/WWW/335/Prions.html) * GSS: Gerstmann-Straussler-Scheinker syndrome * FFI: Fatal familial Insomnia * Kuru “tremble" Fore highlands of New Guinea (1950’s) (No new infections noted since 1959) * Alpers Syndrome AS WITH ANIMALS, THIS LIST IS EXPANDING WITH NEW HUMAN PRION RESEARCH. IT’S A BRAND NEW FIELD.

Summery:-Prions are small protein segments from membranes -In the presence of infectious prions, non-infectious prions become “reconformed” and infectious.-Normal Prions seem Ok. It’s the twisted ones that affect other Prions, aggregate, and cause damage. Chemically, both Prions are the same!!-Transgenic mice without any Prion incidence are used to distinctly show Prion infection.-Human Infection route: eating contaminated meat/nerve tissue.-Disease now known to affect heart of mice.-Human incidence of infection estimated 1-10,000, but this figure is believed to be low.: 

Summery: -Prions are small protein segments from membranes -In the presence of infectious prions, non-infectious prions become “reconformed” and infectious. -Normal Prions seem Ok. It’s the twisted ones that affect other Prions, aggregate, and cause damage. Chemically, both Prions are the same!! -Transgenic mice without any Prion incidence are used to distinctly show Prion infection. -Human Infection route: eating contaminated meat/nerve tissue. -Disease now known to affect heart of mice. -Human incidence of infection estimated 1-10,000, but this figure is believed to be low.

The Handout for this presentation available at:http://firestormer.com/PrionDisease.htm http://firestormer.com/PrionDisease.pptAdditional References:Team Finds Crucial Protein Role In Deadly Prion SpreadEvidence builds that virus spurs mad cowBoffins reverse 'mad cow disease' in micehttp://www.thisislondon.co.uk/news/article-23383811-details/Boffins%20reverse%20'mad%20cow%20disease'%20in%20mice/article.dohttp://www.organicconsumers.org/madcow.cfmhttp://www.pbs.org/wgbh/nova/madcow/http://www.whyfiles.org/012mad_cow/http://www.fda.gov/oc/opacom/hottopics/bse.html: 

The Handout for this presentation available at: http://firestormer.com/PrionDisease.htm http://firestormer.com/PrionDisease.ppt Additional References: Team Finds Crucial Protein Role In Deadly Prion Spread Evidence builds that virus spurs mad cow Boffins reverse 'mad cow disease' in mice http://www.thisislondon.co.uk/news/article-23383811-details/Boffins%20reverse%20'mad%20cow%20disease'%20in%20mice/article.do http://www.organicconsumers.org/madcow.cfm http://www.pbs.org/wgbh/nova/madcow/ http://www.whyfiles.org/012mad_cow/ http://www.fda.gov/oc/opacom/hottopics/bse.html