L8 Prions and TSE Flashcards by Yasmin Yau

what are prion diseases

group of fatal neurodegenerative disorders

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what do prions infect

humans and animals

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where does the prion disease affect

CNS neurodegeneration usually with spongiform change – PrPSc accumulation

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how are prions transmitted

experimentally

naturally

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what is the histology of normal cerebellum like

no gaps between cells here

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what is the histology of spongiform cerebellum

Vacuoles within cells = give brain characteristic spongy texture

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what are prion diseases known as

spongiform encephalopathies

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what do prions affect

brain

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what is transmissible dementias

dementia is a cardinal feature of these transmissible features

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what transmissible spongiform encephalopathies/transmissible dementias/prion diseases infect humans

kuru
creutzfeldt-jacob disease
gerstmann-straussler syndrome

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what is BSE

bovine spongy forming encephalopathies

infects cows

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what is scrapie

prion disease that infects sheep

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what is TME

prion disease that infects mink

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what is chronic wasting disease

prion disease that infects mule deer, elk

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what are TSE proteins sensitive to

proteases
SDS
phenol

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what are the TSE nucleic acids resistant to

nucleases (DNase, RNase)					
ionising or UV irradiation				
psoralen photoadducts			
hydroxylamine					
aldehydes

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what do TSE causative agents include

protein
no evidence causative agent contains nucleic acid
scrapie associated fibrils
PrP 27-30

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how can TSE have reduced infectivity

treat in a way to alter protein structures

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what is SAF

scrapie-associated fibrils

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what are the single protein species in scrapie

PrP27-30

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what is PrP from

PrP33-35

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where is PrPc present

it is a normal cellular gene that we all have encodes PrPc

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which PrP 33-35 is sensitive to proteinaseK

PrPc 33-35

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what is PrPSc 33-35 digested to

proteinase K resistant digested to PrP 27-30 and no further digestion

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what causes prion disease

when PrP27-30 is made and no further digestion leads to accumulation

what causes scrapie

PrPSc accumulates in scrapie infected brains

what differs in the brain of infected and normal

infective brain is protease resistant but normal brain is sensitive – different protein structure of PrPC

what are the PrP isoforms

PrPC 33-35 | PrPSc 33-35

when is there change in the PrP isoforms

post translational

what is the biochemical difference to PrP isoforms

none | same gene sequence, mRNA, amino acid sequence

what happens when PrPc is present in infected = lifecycle

PrPC sporadic structural change to PrPSc PrPSc digested to PrP27-30 and is stuck PrP27-30 catalyses conversion of PrPC into PrPSc = large amounts of indigestible PrP27-30 = neurodegenerative disease

what are the routes of infection for scrapie

intra-cerebral oral – spread along vagus nerve to brainstem OR splanchnic sympathetic nerves to spinal cord accumulation in lymphoid tissue e.g. spleen

what does Kuru, CJD and GSS cause

dementia | cerebellar syndrome

what is the incubation period for Kuru like

5-40 years

how are kuru, CJD, GSS diagnosed

clinical | brain has spongy characteristic post mortem

how long is survival with kuru, CJD, GSS

less than a year

where are human TSEs present

global

how many cases of human TSEs are there

1 million a year (not common disease)

is it genetic disease

familial forms (some patients that develop it have a family history)

what is the age at onset for human TSEs

7th decade

what is the change in the PrP to make it a scrapie one

have a specific gene | protein converting into scrapie conformation misfolding of protein

what is the cause of GSS

chromosome has a leucine present | whereas normal one doesnt

what is the cause of familial CJD

has a lysine present

what causes iatrogenic CJD

modern medicine - corneal transplant - eeg electrodes not sterile into brain - neurosurgery - dura mater graft (dura meter fill holes when part brain removed contains CJD) - human pituitary-derived hormones

ways to get CJD

inherit mutated prion gene prion protein turns to scrapie form modern medicine can cause it

how was scrapie treated

FSH pituitary derived hormone

when was bovine spongiform encephalopathy identified

1986

how is ovine/bovine spongiform encephalopathy transmitted

ingestion of contaminated meat/bone meal

how does vCJD differ to CJD

younger age onset of new variant CJD – looks like new disease in younger people

what did all vCJD have

all in methionine 129 homozygotes

what is the vCJD prion from

BSE

what is the treatment course length for vCJD

average 14 months

what is the prion distribution like in vCJD

distribution unusual – found in peripheral lymphoid tissue preclinically florid plaques within brain

where is it thought people caught vCJD

eating meat

if you were MM% PRNP codon 129 what is it likely you would get

vCJD 100% or 62% sCJD

how many are incubating vCJD

1 in 2000

how can vCJD be spread - secondary

secondary spread e.g. via blood donation, surgical instruments

how are vCJD studied

tonsillectomy studies – stain for abnormal prion protein

what does PrP stand for

prion protein

where does the word prion come from

proteinaceous infective material

what is the PRPC -C suffix mean

cellular prion protein

what is the PRPSc -Sc suffix mean

scrapie

what is the PRPres -res suffix mean

resistant

what causes the spongiform texture

intracellular vacuoles

what is the role of the gene in prions disease

non they are the same as in healthy cells

what is the role of mRNA in prions disease

non they are the same as in healthy cells

what is the role of protein in prions disease

healthy cells = PrPC, protease sensitive | infected cells – PrPSc or PrPRes, protease resistant

what is the difference between the healthy and infected protein

3D structure has 40% more beta sheets

what is the difference between the PrPC and PrPSc

there is post translational changes | no biochemical difference found

how many PrPSc are needed for neurodegenerative disease

1 as the loop is continuous

what happens if PrP27-30 injected into healthy person

PrPC forms PrPSc and continuous cycle and causes own accumulation

how is scrapie treated

no treatment

what is the cause of sporadic CJD

there are no mutations

what is the annual risk of PrPC to PrPSc conversion

1 in a million

what is the risk of PrPSc generation if have familial CJD mutation

1 in 1

what happened when it was found that cows were spreading scrapie

ban on meat/bone meal 1988

what was the problem with the ban of meat/bone meal

cattle had consumed it already so were infected

what are the amino acids at PRNP codon 129

encode methionine or valine | Inherit one from mother and one from father = can be MM / MV / VV