creutzfeldt-jakob disease (prion-based disorders)

Question 1

describe the first discovery of prion diseases

Answer 1

• 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

Question 2

prion diseases are also known as:

Answer 2

transmissible spongiform encephalopathies (TSEs)

Question 3

prion diseases are rare or common? what is the prognosis of this type of disease?

Answer 3

• rare

- fatal - may not appear for a bit but then progesses very fast

Question 4

what type of disease is this?

Answer 4

neurodegenrative

Question 5

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?

Answer 5

• PNRP - chromosome p20
• produces prp
• thought to be involved in maintaining synapses or synaptogenesis (function is unknown)

Question 6

how do prion diseases come about?

Answer 6

the prion protein misfolds, resulting in protein deposition in the brain, causing the progressive neurological disorder

Question 7

how do prion diseases propagate?

Answer 7

by transmitting conformational changes within the prion protein

Question 8

are prion proteins highly or barely conserved among species?

Answer 8

highly

Question 9

describe the non-pathological prion protein (PrP)

Answer 9

• rich in alpha helicies
• protease sensitive
• detergent soluble

Question 10

describe the pathogenic prion protein (PrPSc)

Answer 10

• rich in beta sheets
• protease resistant
• insoluble

Question 11

what are the three ways in which a conformational change within a prion protein can manifest?

Answer 11

(1) infectious PrPSc
(2) mutation PrPM
(3) sporadic PrPSc

Question 12

describe infectious PrPSc

Answer 12

• 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

Question 13

describe mutation PrPM

Answer 13

• 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

Question 14

describe sporadic PrPSc

Answer 14

• 85%
• conformational changes within the prion protein can also be sporadic
• this means its unknown what factors cause it

Question 15

increased presence of beta sheets found in misfolded prion proteins results in what?

Answer 15

changes to the structure of brain tissue

Question 16

what are the pathologies associated with prion diseases? (what are the associated changes to brain tissue?) (5)

Answer 16

(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

Question 17

how does spongiform encephaly occur?

Answer 17

• the formation of fibrils from prion depositions results in the formation of amyloid plaques
• this affects dendrite and neuronal function, creating gaps

Question 18

what disease represents ~85% of all prion diseases?

Answer 18

CJD

Question 19

is there any gender predilection to CJD?

Answer 19

no

Question 20

list and describe the four subtypes of CJD

Answer 20

(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

Question 21

what are the symptoms of sCJD?
how long to patients live with this disease?
what is the typical age of onset?

Answer 21

• dementia, ataxia, myoclonus
• <1 year
• 61

Question 22

what are the symptoms of vCJD?
how long to patients live with this disease?
what is the typical age of onset?

Answer 22

• behavioural changes, dementia
• 1.5 years
• teens/young adults

Question 23

what are the symptoms of iCJD?
how long to patients live with this disease?
what is the typical age of onset?

Answer 23

• ataxia, dysarthria, dementia
• 2-6 years
• 20s-60s

Question 24

what are the symptoms of fCJD?
how long to patients live with this disease?
what is the typical age of onset?

Answer 24

• insomnia, dysautonomia, ataxia, dementia
• 1 year
• 45

Question 25

what would a typically histological stain look like for sCJD?

Answer 25

- typical spongiform degeneration of the gray matter | - reactive gliolisis

Question 26

what would a typically histological stain look like for vCJD?

Answer 26

florid plaques consisting of dense core prion deposits surrounded by vaccuoles (halo)

Question 27

what would a typically histological stain look like for iCJD?

Answer 27

large prion protein amyloid plaques

Question 28

what would a typically histological stain look like for fCJD?

Answer 28

- neuronal loss and gliolisis in the thalamus, inferior olives of the medulla and cerebellum - no vacuolar degeneration

Question 29

how did we test the idea that vCJD is caused by BSE?

Answer 29

- 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)

Question 30

is there any cure or certified treatment available to slow the progression of prion diseases? is early diagnosis important? why or why not?

Answer 30

- no - yes - so family can come to terms with the diagnosis

Question 31

what is an optional experimental treatment? how does it work?

Answer 31

-oxygen therapy - uses hypoxia to increase gene expression of the non-infectious prion protein and provide beneficial effects on the affected neurons

Question 32

what can be done to confirm CJD after death?

Answer 32

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