L6 Pathology Prion disease Flashcards
how is the post mortem examination carried out
high risk
dedicated equipment
full protective gear: visor, double gloves, safety boots
what findings lead to protein only hypothesis
no viral particles detectable
no significant inflammatory or immunological reactions of the host
deposition of an abnormal protein, often in form of plaques
infectivity is associated with the protein deposits
damage to nucleic acids does not inactivate infectivity
extraction of the protein fraction abolishes infectivity
what is Prusiner 1982 hypothesis
the plaque protein is the infectious agent
what is the Weissmann 1985 hypothesis
the normal non-infectious protein PrP^c is encoded by the host (cellular form of PrP)and mainly expressed on neurons
what is the protein only hypothesis
the infectious prion protein has the same amino acid composition, but is resistant to proteases and tend to ploymerise
what are thermodynamic assumptions
there is conversion prevented by energy barrier between PrP^c and PrP^sc
or there is equilbrium
what happens in seeding and
if there is an excessive production of this misfolded form, you have a seed formation and that recruits further seeds built up to an infection seed then fragments into infectious seed or amyloid
what is not essential in template directed refolding
amyloid not essential for replication
what is the definition of prion
Agent of transmissible spongiform encephalopathy (TSE), with unconventional properties.
The term does not have structural implications other than that a protein is an essential component
what is the definition of PrP^c/PrP^sen
The naturally occurring form of the mature Prnp gene product. Its presence in a given
cell type is necessary, but not sufficient, for replication of the prion
what is the definition of PrP^sc or PrP^res
Abnormal’ form of the mature Prnp gene product. Partly resistant to digestion by
proteinase K.
Believed to differ from PrPC conformationally. Often considered to be the transmissible agent or
prion.
how many amino acids are in the PrP isoforms
209
what is the primary translation product and how many anchors needed for the glycosilation
primary gene product with the signal peptides
3 gpi
what happens in a mature PrP
primary translation/gene product matures and the signal peptide is taken off
the cellular formis protease sensitibe- breaks down into fragemnts
what happens in PrP^sc
the abnormal form with misfolded proteins with same primary structure and no other amino acids is now partially resistant to proteases - can be used as detection
prp-res for resistant
what is the corollary to the protein only hypothesis
Prnp knockout mice are resistant to scrapie
presence of abnormally folded protein, leads to the production of more abnormally folded protein
take awaysubstrat eshould be no more product
- this was experimentded in 1991 - generated mice
name a sporadic form of prion disease
Creutzfeldt-Jakob Disease
name hereditary forms
Familial CJD and Gerstmann-Sträussler-Scheinker-Syndrome
– Fatal familial insomnia
name transmitted forms
Kuru (ritual cannibalism in New Guinea) – Medical procedures (Iatrogenic CJD) • contaminated growth hormone • Dura mater graXs, cornea graps • Surgical instruments, EEG electrodes – Variant CJD (BSE epidemics
how many polymorphism does prion gene have
2
what is seen microscopically in CJD
neuronal loss spongiosis gliosis Fine spongiform changes in the cortex, and synaptic PrP Macrovacuoles, coarse PrP Cortical ribbon, perineuronal net
what gss phenotype forms plaques in PRNP gene
P1OL
P1O5L
what can form in prp deposition patterns
gss
where are vCJD prions detectable in BSE
detectable in the lymphore;cular system (e.g. tonsils, appendix),
thought to precede CNS
invasion
within the follicular dendritic cells there’s abnormal prion patients who acquire BSE
how many glycosilation trees does the prp gene production have
none, 1 or 2
where is the distribution of abnormal PrP in human tissues in body of variant
brain eyes sympathetic ganglia tonsil lymph nodes spinal cord spleen adrenal rectum
what is the clinical feature or kuru
progressive cerebellar ataxia
what does kuru resemble
iatrogenic CJD caused by peripheral administration of contaminated growth hormone
how can prion diseases transmit through medical procedures
More than 200 cases of Creutzfeldt-Jakob disease (CJD) have resulted from
treatment with human cadaveric pituitary-derived growth hormone
contaminated with prions
• Approximately 200 cases of CJD resulted from the transmission through
dura mater grafts
• Electrodes, cornea grafts, surgical instruments
• Blood transfusion
who did studies on kuru to primates
The agent was previously thought to be a slow virus
• But it had rather unusual biological proper;es.
• Transmission studies were carried out in primates (Gajdusek, Gibbs, Alpers 1967)
• The findings led to the proposi;on of the protein only hypothesis (Griffith 1967)
in what ways can the disease be iatrogenic
vCJD blood transfusion gonadotroph hormone corneal grafts neuro-surgical instruments dural grafts growth hormone
