creutzfeldt-jakob disease (prion-based disorders) Flashcards
describe the first discovery of prion diseases
- in Kuru
- found that there was a pre-clinical stage and 3 clinical stages (ambulent, sedentary, terminal)
- found that it mostly affected women
- classified by spongiform encephalopathy and plaques
- did not cause inflammation
- was tied to canabolism at the time
prion diseases are also known as:
transmissible spongiform encephalopathies (TSEs)
prion diseases are rare or common? what is the prognosis of this type of disease?
- rare
- fatal - may not appear for a bit but then progesses very fast
what type of disease is this?
neurodegenrative
what is the prion gene and where is it encoded?
what is the normal cellular protein this gene produces?
what is the function of this protein?
- PNRP - chromosome p20
- produces prp
- thought to be involved in maintaining synapses or synaptogenesis (function is unknown)
how do prion diseases come about?
the prion protein misfolds, resulting in protein deposition in the brain, causing the progressive neurological disorder
how do prion diseases propagate?
by transmitting conformational changes within the prion protein
are prion proteins highly or barely conserved among species?
highly
describe the non-pathological prion protein (PrP)
- rich in alpha helicies
- protease sensitive
- detergent soluble
describe the pathogenic prion protein (PrPSc)
- rich in beta sheets
- protease resistant
- insoluble
what are the three ways in which a conformational change within a prion protein can manifest?
(1) infectious PrPSc
(2) mutation PrPM
(3) sporadic PrPSc
describe infectious PrPSc
- 1%
- if a patient is exposed to the pathogenetically folded prion protein it will cause the proteins that dont have the conformation to assume that conformation
- once this begins there is continuous cascade of pathogenesis
describe mutation PrPM
- 15%
- conformational changes within the prion protein can be genetic
- this means there’s a change in the aa seq that results in an increased susceptibility to form misfolded proteins
describe sporadic PrPSc
- 85%
- conformational changes within the prion protein can also be sporadic
- this means its unknown what factors cause it
increased presence of beta sheets found in misfolded prion proteins results in what?
changes to the structure of brain tissue
what are the pathologies associated with prion diseases? (what are the associated changes to brain tissue?) (5)
(1) prion deposition in the brain - can lead to other pathologies:
(2) synaptic dendrite loss
(3) spongiform encephaly - prion diseases make the brain look like a sponge (holes are produced in the brain tissue)
(4) gliolisis - proliferation of glial cells (occurs in response to (injury) the deposition of amyloid plaques)
- if this persists it leads to scarring within the brain
(5) neuronal death - can spread to other organs
how does spongiform encephaly occur?
- the formation of fibrils from prion depositions results in the formation of amyloid plaques
- this affects dendrite and neuronal function, creating gaps
what disease represents ~85% of all prion diseases?
CJD
is there any gender predilection to CJD?
no
list and describe the four subtypes of CJD
(1) sporadic CJD (sCJD): most common
- cause is unclear
(2) variant CJD (vCJD):
- caused by consuming contaminated meat from a cow with spongiform encephalopathy (BSE)
(3) iatrogenic CJD (iCJD): rare
- caused by a medical examination or treatment
(4) familial CJD (fCJD): rare
- mutated prion gene is passed down from patient to child
what are the symptoms of sCJD?
how long to patients live with this disease?
what is the typical age of onset?
- dementia, ataxia, myoclonus
- <1 year
- 61
what are the symptoms of vCJD?
how long to patients live with this disease?
what is the typical age of onset?
- behavioural changes, dementia
- 1.5 years
- teens/young adults
what are the symptoms of iCJD?
how long to patients live with this disease?
what is the typical age of onset?
- ataxia, dysarthria, dementia
- 2-6 years
- 20s-60s
what are the symptoms of fCJD?
how long to patients live with this disease?
what is the typical age of onset?
- insomnia, dysautonomia, ataxia, dementia
- 1 year
- 45
what would a typically histological stain look like for sCJD?
- typical spongiform degeneration of the gray matter
- reactive gliolisis
what would a typically histological stain look like for vCJD?
florid plaques consisting of dense core prion deposits surrounded by vaccuoles (halo)
what would a typically histological stain look like for iCJD?
large prion protein amyloid plaques
what would a typically histological stain look like for fCJD?
- neuronal loss and gliolisis in the thalamus, inferior olives of the medulla and cerebellum
- no vacuolar degeneration
how did we test the idea that vCJD is caused by BSE?
- brain extracts of vCJD and BSE were put into mice and then treated with proteinase K and the migration patterns were examined using western blots
- sCJD and iCJD displayed same patterns (type1-3)
- vCJD and BSE displayed the same patterns (type 4)
is there any cure or certified treatment available to slow the progression of prion diseases?
is early diagnosis important? why or why not?
- no
- yes
- so family can come to terms with the diagnosis
what is an optional experimental treatment? how does it work?
-oxygen therapy - uses hypoxia to increase gene expression of the non-infectious prion protein and provide beneficial effects on the affected neurons
what can be done to confirm CJD after death?
autopsy:
- western blot of proteins
- brain slices can confirm via the gross anatomy of the brain (spongy, sCJD =ventricles that are more widely spaced, etc.)
- often see atrophy (dilation of the ventricles) due to the loss of neuronal matter
