Pathology of CJD Flashcards
What are the findings that lead to protein-only hypothesis?
- No viral particles detectable
- No significant inflammatory/immunological reactions of the host
- Deposition of an abnormal protein, often in form of plaques
What is infectivity associated with?
Protein deposits
What does not inactivate infectivity?
Damage to nucleic acid
What abolishes infectivity?
Extraction of the protein fraction
What is the Protein-only Hypothesis?
- Prusiner 1982: the plaque protein is the infectious agents
- Weissmann 1985: the normal, non-infectious protein (PrPC) is encoded by the ost and is mainly expressed on neurons
- The infectious prion protein (PrPSC) has the same amino acid composition, but is resistant to proteases and tends to polymerise
What are the different types of transmission?
- Medical procedures
- Kuru
- Exogenous PrP is internalised into the cell
- During internalisation, replication takes place
- Formation of externally acquired prions - transmitted forms
What mutations leads to an exchange of an amino acid and more prone to misfolding?
Specific mutations in the open reading frame of the gene
What do abnormal protein form?
Aggregates and essentially clogs up the cell
Define prion
Agent of transmissible spongiform encephalopathy (TSE), with unconventional properties. The term does not have structural implications other than a protein is an essential component
Define PrPC or PrPsen
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
Define PrPSC or PrPres
Abnormal form of the mature PrnP gene product
Partly resistant to digestion by proteinase K
Believed to differ from PrPC conormationally. Often considered to be the transmissible agent or prion
What includes the signal peptide?
primary gene products
How many achors are there for the glcosylation trees?
3 GPI anchors
When are the signal peptides taken off?
When the primary gene product matures
What are protein sensitive?
Cellular form of PrP
What can be used as an detection for protease?
The misfolded form which has the same primary structure, it is partly resistant to the proteases
What are the 3 different types of prion disease?
- Sporadic forms: Creutzfeld-Jakob Disease
- Hereditary forms
- Transmitted forms: human and zoonotic
What are examples of hereditary forms?
- Familial CJD and Gertsmann-Straussler-Scheinker-syndrome
2. Fatal familial insomnia
What is an example of transmitted form?
Kuru (ritual cannabalism in New Guinea) Variant CJD (BSE epidemics)
What are medical procedures (Iatrogenic CJD)
- Contaminated growth hormone
- Dura mater grafts, cornea grafts
- Surgical instruments, EEG electrodes
What are features of normal cortex?
- Neuronal nuclei and astrocytes
* In between neuropil and consists of dendrites and axons and synapses forming between neurons
What are features of CJD?
- Terminal form of CJD
- Neurons are gone
- Form larger cytoplasm
What are the GSS phenotypes?
- P102L
2. P105L
What forms a lot of plaques?
A117V
What is a stop codon that is not transmissible?
Y145-stop
forms a lot of amyloid
Transmission of prion disease I
- BSE epidemics in the 1980’s and 1990’s
- Widespread dietary exposure of the UK population to BSE prions in the late 1980’s and early 1990’s
- Emergence of variant CJD in the mid 1990’s
- vCJD prions detectable in the lymphoreticular system (e.g. tonsils, appendix) thought to precede CNS invasion
What does different prion strains correlate with?
Different PrPsc glycopatterns
- Diglycosylated
- Monoglycosylated
- Unglycosylated
What prion disease are mono-glycosylated dominant?
- sCJD type 1 and 2
- ICJD
- Kuru
What are vCJD and BSE prions ?
di-glcosylated dominant
What are vCJD distribution in the body?
- Brain
- Eyes
- Sympathetic ganglia
- Tonsils
- Lymph nodes
- Spinal cord
- Spleen
- Adrenal
- Rectum
What regions do kuru and sporadic CJD include?
- Brain
2. Spinal cord
Where do BSE prions settle down?
Lymphoreticular tissues
What is spleen important for?
Proportion of the gut including the appendix
appendix is small protusion of gut - contains those lymphoid follicles
What resulted in human-human prion transmission?
Fore kinship groups consumed deceased relatives at mortuary feasts
Who did Kuru predominantly affect?
Women and children (of both sexes) with only 2% of cases in adult males
What is the central clinical feature of Kuru and Iatrogenic CJD?
Progressive cerebellar ataxia
What does KURU most closely resemble?
Iatrogenic CJD caused by peripheral administration of contaminated growth hormone
How has Transmission of CJD in industrialised countries occured?
Accidental inoculation with human prions as a result of medical and surgical procedures
What did more than 200 cases of CJD resulted from?
Treatment with human cadaveric pituitary-derived growth hormone contaminated with prions
What do approximately 200 cases of CJD result from?
Transmission through dura mater grafts
Transmission of prion diseases: kuru into primates
- The agent was previously thought to be a slow virus
- But it had rather unusual biological properties
- Transmission studies were carried out in primates
- The findings led to the proposition of the protein only hypothesis
