Prions and Transmissible Spongiform Encephalopathies

Question 1

Identification of spongiform encephalopathy

Answer 1

first in papa New Guinea at Kuru epidemic; disease was being spread by endocanibalism

Question 2

Kuru shares similarities with

Answer 2

CJD (rare human neurodegenerative disease) and scrapie; CNS degeneration with areas of brain becoming vacuolated or spongy, extensive deposition of fibrils or plaques

Question 3

CJD

Answer 3

rare human neurodegenerative disorder; onset at 60; 10-15% cases are inherited; shown to have infectious nature in 1968 when cerebral innoculations from CJD patients performed on non-human primates; was transmitted through human growth hormone

Question 4

Kuru experiment on chimps

Answer 4

saw signs 18-21 months after cerebral inoculation in non-human primates

Question 5

Koch’s postulation of causation

Answer 5

1. causal agent should be found in animals suffering from dx not healthy animals
2. when isolated from dx animal and inoculated into susceptible animal dx with characteristic symptoms and clinical outcome should result
3. should be possible to reisolate same causal agent from experimental animals to demonstrate chain of transmission

Question 6

Identification prion protein

Answer 6

used Syrian hamster bioassay; brain extractions to purify infectious agent;PrP identified as protease resistant protein uniquely present in scrapie brain

Question 7

prion

Answer 7

proteinaceous infectious particle that lacks nucleic acid passed on via epigenetic inheritance

Question 8

epigenetic inheritence

Answer 8

infectious agents passed form mother cell to daughter cell with no dependence on RNA or DNA; violated previously accepted rule that inheritance and infection had to require RNA or DNA

Question 9

Prion protein encoded by

Answer 9

PRNP gene (=PrPc) (proteins come from genes genes are transcripts from RNA)

Question 10

PRNP and prion disease

Answer 10

PRNP= PrPc is delted in mice they are completely resistant to prion infection, if PRNP transgene reintroduced then they are once again susceptible; over expression PrP in old wild type mouse leads to spongiform dx; PRNP essential component of infectious prion

Question 11

PrPc and PrPsc

Answer 11

AA sequence of both are identical and there are no post translational modifications the difference is in the way they fold, PrPc has alpha helices and is globular , PrPsc has beta sheets

Question 12

PrPsc conformation and disease

Answer 12

PrPsc has beta sheets instead of alpha helices and is not globular like PrPc; B sheets can form protease resistant, insoluble fibrils by hydrogen bonding between B sheets; accumulation of fibrils in plaques can cause cell death and neurodegeneration

Question 13

amyloid

Answer 13

protein accumulation (plaque formed by fibrils); amyloid is the abnormal staining deposit name in path exam

Question 14

why is PrPc needed to develop prion dx

Answer 14

PrPsc induces PrPc to chance conformation bc of hydrophobic AAs and converts it into PrPsc and accumulates into fibrils its v rare to have globular PrPc to conformational change without PrPc causing it

Question 15

heterodimer

Answer 15

PrPsc beta sheet with PrPc globular protein

Question 16

homodimer

Answer 16

2 PrPsc beta sheet structures together

Question 17

Biological roles of prion domain conversion

Answer 17

1 example is spider web, goes from alpha helices to beta sheets between storage and web making

Question 18

human diseases similar to CJD

Answer 18

GSS syndorme and fatal family insomnia

Question 19

polymorphysims of PRNP

Answer 19

CJD- cerebral cortex
FFI- thalamus
Kuru, Gss- cerebellum
BSE- brainstem

All related to prion gene but effect diff regions of brain and have different symptoms because of small subtile AA changes

Question 20

Prion strains phenotypic differences

Answer 20

incubation times, histopathological lesion profiles, and specific neuronal target areas; phenotypic traits typically persist upon serial transmission

Question 21

prion broad deffinition

Answer 21

protein that infinitely propagates an altered form of itself without DNA or RNA; propagation of protein is transmissible

Question 22

Psi

Answer 22

yeast prion; when cells have Psi they’re white when they don’t they’re red if treated with unfolding agent they can go from white to red bc cells given a chance to fix misfolded proteins; indicates we may be able to see if chaperones can help with misfiled proteins in people with TSE

Question 23

what is happening at the molecular level dominant epigenetic inheritance

Answer 23

normal proteins can produce folding intermediates with sticky surface which acts as template to bind and trap other partially unfolded proteins newly synthesized proteins can get trapped in the aggregate; aggregates are passed to successive generations of cells through cytoplasm to propagate disease

Question 24

other neurodegenerative conditions associated with spongiform like changes in CNS

Answer 24

Prion dx, alzheimers, Parkinson’s, frontotemporal dimensia, Picks dx, progressive supra nuclear palsy, ALS, Huntinton’s, spinocerebellar ataxias
These are all due to aberrant proteins proteinneuropathies that eventually lead to cell toxicity and degeneration

Question 25

Alzheimer’s

Answer 25

insoluble plaques of amyloid and neurofibrally tangles; genetic predispositions (specific mutations associated with familial forms of early onset alzheimers (increased beta amyloid); amyloid accumulation in brain associated with polymorphisms

Question 26

Huntington’s disease

Answer 26

codes for polyglutamine which leads to repeater of sticky glutamine (coded for by CAG) that leads to prion like properties that leads to aggregation and neurotoxicity; this is genetic disorder

Question 27

mouse model huntingtons

Answer 27

can turn hd gene on and off; turn off to stop production of protein halts disease progression and can reverse aggregate formation

Question 28

polyglutamine tract aggregation yeast

Answer 28

causes cell death in yeast model (toxic single cell aggregation)

Question 29

aggregation phenotype depends on (in PolyQ aggregation)

Answer 29

depends on there being another prion protein present in the cell (Huntington’s requires presence of a prion); prions induce aggregation of other proteins/ prions

Question 30

adult onset neurodegeneration

Answer 30

neurodegenerative disease have long latency; mechanism of proteinopathy type diseases similar in principle to what we know about prion dxs; complex interplay of contributing factors to developing protein aggregates (if excellent proteins chaperones may not have same level of aggregates)

Question 31

alzheimers dx propigation

Answer 31

propigated in prion like fashion with cerebral extractions

Question 32

Kuru survivors

Answer 32

found to have higher levels of AA at one position that effects spongiform and prion susceptibilities mice were resistant to prion dx when inoculated with this

Question 33

Kuru surviviors relation to public health

Answer 33

related bc of vCJD and BSE need to known about prion susceptibility if a TSE comes back in epidemic form

Question 34

outstanding questions from TSE research

Answer 34

why do we have PrPc, why does PrPsc effect brain/ NS, what is prion uptake/ distribution method between cells, molecular structures of prion oligomers and amyloid fibers, relationship between protein fibrils and neurotoxicity, cell mechanisms to deal with protein aggregation, how can prions affect other proteins aggregating, what determines interspecies susceptiblity

Question 35

CLassifications of transmissible spongiform encephalopathies

Answer 35

acquired- horizontal transmission; CJD, Kuru, CWD, BSE, vCJD, TME, feline spongiform encephalopathy, iatrogenic transmission
Familial- vertical transmission, inherited from cell to cell and via predisposing mutations transmitted from parent to offspring (CJD, FFI, GSS, BSE, Scrapie)
Sporadic- idiopathic prion disease can arise spontaneously (CJD)