Prion Diseases

Question 1

Prion protein (PrPC):

Answer 1

proteins that occur naturally in the brains of animals and people, maintain the myelin sheath that protects the body’s nerves.
On cell surface

Question 2

Prp* or PrPSc

Answer 2

: abnormal, misfolded form of prion protein

Question 3

Normal vs Abnormal Prion protine structure

Answer 3

normal - alfa helecies
Abnormal - more betta sheets

Question 4

Mice with knockout (no Preion gene) what happens if exposed to ablormal prion population

Answer 4

nothing because abnormal needs normal to mutate/cause aggregates

Question 5

why are aggregates toxic to cells

Answer 5

toxic, kills cells, exact mechaism unknown

Question 6

formation of Amolic Fibrils

Answer 6

positive feeback loop

Question 7

FFI

Answer 7

Thalamus

fatail famileal insomina

interated sleeping patterns - long incubation period - dont see till 40s and 50s

Question 8

BSE

Answer 8

Brain stem

Mad cow disease - cows act strange - unstable gait and agressive

aquired - giving animals other animals to eat (eating the abnormal prion)

Question 9

CJD

Answer 9

crebral cortex

Creutzfeldt-Jakob Disease

vCJD- varent - aquired

long incubation periods - once diseasse shown - rapid progression - life expectancy in months

varent medain age of death 28years, classic 68

Prominent psychiatric/behavioral symptoms (anxiety, depression)

Unsteadiness, difficulty walking, involuntary movements, difficulty swallowing, blurred vision, impaired thinking, memory loss, difficulty speaking

Rapid deterioration (months), heart failure, respiratory failure, pneumonia or other infections are generally the cause of death. Most lapse into a coma. Death usually occurs within a year.

Question 10

KURU

Answer 10

Cerebellum

unsteady gate, oncontrolable tremors, emotions (unconrolable laughter)

rapid progression - positive feeback look

beleved to be caused by canabilism

Question 11

Models of how an infectious prion cause another protein to misfold?

Answer 11

1. Abnormal prion activates enzyme that converts normal prion to abnormal form.
2. Other cofactors assist in the stabilization of amyloid fibrils
3. PrpSc binds and catalyzes conversion of PrpC to PrpSc

Question 12

Why is the brain vonureble to amyloid fibrils/placks

Answer 12

Quality control mechanisms governing proteins gradually decline with age, which may permit protein aggregates.

The brain is composed of highly organized nerve cells that cannot regenerate, and is therefore vulnerable to this damage (susceptibility to neurodegenerative disease)

Question 13

Causes of Prion disease

Answer 13

1. Inherited: Mutation in prion gene (FFI)
2. Sporadic: Normal prion misfolds to abnormal prion (1/million) - most common
3. Acquired: results from exposure to PrPSc from an outside source (Kuru, mad cow, varent CJD)

Question 14

Mad cow prevetion

Answer 14

• Removed parts of cow that can be processed for food (brain and spinal cord)
• Servalance using mice – lower brain weight – lower incubation period)
• Restrictions on cattle importation
• FDA responsible for animal feeds

Question 15

Diagnosis of vCJD

Answer 15

Exclusion of other neurodegenerative diseases (CJD progresses rapidly, others much slower)

Detectable 14-3-3 protein in the cerebrospinal fluid (CSF) is indicative of substantial, relatively rapid neuronal destruction

Conformatory diagnosis : post mortem

New tests in blood being devoloped - abnormal prions in blood v v low concentraions

Question 16

vCJD treatment

Answer 16

comfort care

(testin new via infestgation of protine only yeast(Proteins can form several different types of amyloid fibrils from
same polypeptide chain), and antibidies (cross BBB) against prions (prions not degraded by proteases or reconized by immune because abnormal)