Evolutionary Microbiology

Chapter 3. Prion – Mad Protein

Jong-Soon Choi

Chungnam National Univ. GRAST

University of Science and Technology

Korea Basic Science Institute

43

Folded and Stacked Chairs

What is Mad Cow Disease?What causes Mad Cow Disease?Why is MCD dangerous to Human?

(Source: www.google.com) 44

Statistics of Bovine Spongiform Encephalopathy (牛海綿樣腦症)

(Source: www.google.com)

45

Scrapie, Mad Sheep Disease

(Source: www.google.com) 46

Papua New GuineaCannibalism

*Carnival(Carne Vale, 사순제)

(Source: www.google.com) 47

Kuru, Laughing DiseaseIn Fore Tribe, Papua New Guinea

(Source: www.google.com) 48

In 1976 Carleton Gajdusek became

co-recipient of the Nobel Prize in

Medicine for his "discoveries

concerning new mechanisms for the

origin and dissemination of infectious

diseases."

(Source: www.google.com) 49

Daniel Carleton Gajdusek(1923~2008, American Physician)

Pathology of Kuru, CJD, scrapie-infected brains(Source: www.google.com)

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Kuru-like Human Brain Diseases

-Creutzfeldt-JacobsDisease-Fatal Familial Insomnia-Gersstmann-Straussler-ScheinkerSyndrome-Bovine SprongiformEncephalopathy

(Source: www.google.com) 51

(Source: www.google.com) 52

What is Prion??

Proteinaceous infectious particle

A nonliving, self-replicating infectious agent made of “Protein”

It can reproduce with the aid of its host’s biological machinery like a Virus.

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Property of Prion

Prion : a propagating

agent composed of

protein

Prion-induced disease :

Mad Cow Disease,

Scrapie, Creutzfeldt-

Jakob Disease,

Gersstmann-Straussler-

Scheinker Syndrome,

Fatal Familial Insomnia,

Kuru (Mad Human

Disease)nucleation

transformationfragmentation

normal

abnormal

amyloid fiber

(Source: www.google.com) 54

Structure of Prion

PrPC : normal form of prion,

alpha-helices readily digestible

by proteinase K

What’s the function of normal

prion?

Cell membrane component,

cell-cell communication in brain?

long-term memory

stem cell renewal

PrPSc : infectious isoform of PrP

a higher proportion of PrP, beta-

sheet, amyloid fiber resistant to

proteinase K heat stable up to

90 Celsius degree

What mediates the transformation of PcPC to PcPSc?

Contaminated human growth hormone (Nature 2015)

HOW?

(Source: www.google.com) 55

Primary Structure of Mouse Prion Protein

-Octarepeat region-Transmembrane region-Three alpha-helical domains

Copper-binding domain Alpha-helix C-terminal domain

Lipid bilayer

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What is Prion?

Infectious agent lacking nucleic acids for reproduction???

Discovery of Fungal Prion

Sup35, yeast translation-

termination factor

Partial LOF of sup35

nonsense suppression

Prion state of Sup35p

phenotype [PSI+] : Amyloid

state of Sup35p

*Amyloid, insoluble fibrous

protein (Source: www.google.com) 57

Sup35

201 amino acids

N-term (Prion-domain),

Middle, C-term

Small bowel

duodenum

With amyloid

deposition,

20X

Oligopeptide repeat PQGGYGG-YN :

prion-determining domain

[PSI+] act as an evolutionary

capacitator for adaptation in

natural population at times of stress!(Source: www.google.com)

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Diseases featuring amyloids

All neurodegenerative disease in brain!!!(Source: Wikipedia)

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Alzheimer disease

Notable cases : C. Heston & R. Reagan1st Described Patient

Changed tau leads to the

disintegration of microtublesNormal aged & Alzheimer’s patient’s brain

(Source: www.google.com) 60

Parkinson’s disease

Handwriting of a PD patient

3D-structure

of Parkin

Lewis body (insoluble

protein aggregates)

deposit in mid brain

Volume reduction in mid-

brain of PD patient

The world’s most

famous PD patient

(signed at 38,

diagnosed at 42,

progressing at now

70)

(Source: www.google.com) 61

Lessons of Prion

What is the advantage of Prion?

Protein-based inheritance

What is the conversion mechanism of PrPC to PrPSc?

Protein X can mediate the conversion.

Is it possible Protein-only hypothesis?

controversial to Central dogma

not found prion-related virus

or bacteria

What on earth is the prion?

possible story???

(Source: www.google.com) 62