Prions

Question 1

History of Transmissible Spongiform Encephalopathy

Answer 1

-1730- Scrapie First Appears
-1950s- Kuru outbreak
-1960s- infectious agent
-1980s- 60 people die from CJD from contaminated from surgical instruments and growth hormone
-1982- PROteinaceous INfectious particle
-1985- our genes encode the protein
1986- outbreak of mad cow disease
-1996- Mad cow disease is found in humans

Question 2

Prion diseases

Answer 2

• Scrapie- sheep and goats
• Cats- feline spongiform encephalopathy
• Deer, elk- chronic wasting disease
• Cattle- bovine spongiform encephalopathy (BSE), mad cow diase
• Humans- Kuru, Fatal familial insomnia, Gerstmann-Staussler-Scheinker syndrome, vCJD, sCJD

Question 3

Creutzfeldt- Jacob Disease

Answer 3

-the most frequent of human prion disease
-causes:
sporadic (cCDJ), no known cause (85-95%)
familial (fCJD), inherited genetic risk (7-10%)
iatrogenic (iCJD), exposure during medical procedures (<1%)
-sCJD can not be transmitted person to person by blood transfusion or meat contaminated with BSE- not related to mad cow disease

Question 4

sCJD symptoms and signs

Answer 4

• sCJD causes spongiform encephalopathy
• loss of brain function resembles Alzheimer’s disease, but is very rapid progression
• complete dementia usually occurs by the sixth month
• death occurs within one year of symptom onset
• mental deterioration and myoclonus (twitch, present at some point during illness)

Question 5

What causes prion diseases

Answer 5

• protein only hypothesis- no virus, bacteria, fungi, no nucleic acid is associated with infectivitiy- resistant to UV radiation and nucleases, no immune response
• some evidence against- skeptics argue diseases like Alzheimers aren’t infectious; thus misfolded protein alone is not enough to transmit disease

Question 6

PrPc Misfolding Causes Encephalopathy

Answer 6

• prions are encoded by the host
• Prnp gene encodes a 35kDa membrane glycoprotein in mammels
• PrPc is involved in maintaining the brains white matter, regulatin innate immune cells, responses to oxidative stress, and neuron formation
• protein misfolding converts PrPc into PrPsc leading to prion disease
• PrPsc can arise by mutation or from exogenous sources (meat, blood)
• PrPsc can be experimentally transmitted between animals
• animals lacking PrPc do not contract prion disease
• PrpSc mechanism of pathogenesis is unknown

Question 7

PrPsc classification

Answer 7

• several human PrPsc types have been identified in brains that are associated with different phenotypes of CJD
• different fragment sizes are observed on Western blots following treatment with proteinase K
• based on the ratio of the 3 PrP bands seen after protease digestion, 4 types of human PrPsc have been identified

Question 8

Model for Prion Self Replication

Answer 8

• prions are infectious, but contain no genetic material
• once formed, the nucleus (seed) recruits other PrPc and converts them to PrPsc
• the nucleus increases in size to become an amyloid fiber
• fragmentation occurs- liberates new ends to allow for amplication, allows the dissemination of infectious material

Question 9

sCJD diagnosis

Answer 9

• brain biopsy- only definitive
• sCJD characterized by spongiform change, neuronal loss without inflammation, accumlation of PrPsc

also

• detection of 14-3-3- protein in CSF
• abnormal MRI and EEG

Question 10

sCJD treatment and prognosis

Answer 10

• no effective treatment
• median disease duration of 5-6 months
• death usually occurs with 1 year

Question 11

sCJD Epidemiology

Answer 11

• from 1979 through 2006, 6917 deaths due to sCJD
• 247 deaths occur annually
• annual incidence has remained stable at 1 case per 100,000
• higher in older population- median 68, most deaths 60-79
• slight majority in women 52.6%
• 94.6% deaths in whites

Question 12

Varient Creutzfeld Jacob Disease

Answer 12

• vCJD is a type 4 prion
• vCJD represents bovine to human transmission of BSE
• in cattle, BSE is transmitted via CNS, retina, the trigeminal and paraspinal ganglia, the distal ileum, and the bone marrow- muscle and milk no BSE

Question 13

vCJD symptoms and signs

Answer 13

• vCJD can have a similar clinical presentation as sCJD
• loss of brain function associated with vCJD progresses slower than sCJD (still more rapid that Alzheimers)
• mean duration is 14 months compared to vCJD versus 4-5 months for sCJD
• vCJD has a peripheral pathogenesis distinct from classical forms of CJD, with prominent involvement of lymphoreticular tisues
• vCJD is fatal

Question 14

vCJD diagnosis

Answer 14

• overall, vCJD is similar to sCJC
• type 4 PrPsc found in patients with vCJD is not found in other human prion diseases
• vCJD has tropism from lymphoid organs such as tonsils
• detection of 14-3-3 protein in CSF is not a sensitive marker for vCJD
• abnormal MRI signal is distinct from those obtained from sCJD patients- slow wave pattern
• abnormal PrP deposition in sCJD presents as diffuse staining whereas vCJD florid PrP plaques consist of a round amyloid core (amyloids are insoluble fibrous protein aggregates) surrounded by a ring of spongiform vacuoles

Question 15

vCJD onset of disease

Answer 15

-mean age at onset of vCJD is 29 years (range 11 to 74 years) compared with 65 years for sCJD

Question 16

Time course of BSE in UK

Answer 16

• the first case of BSE was diagnosed in 1986
• ban on animal feed that contained animal ruminants was introduced in 1988
• ban on specific bovine offal (SBO) introduced in 1991- brain, spinal cord, thymus, spleen and intestine
• by 1992, these bans started to bring the BSE epidemic under control

Question 17

Incidence of BSE and vCJD in Great Britain

Answer 17

• BSE epidemic peaked in 1992, 4 years after the introduction of the ban on ruminant feed
• currently, BSE is trailing down to extinction
• vCJD was not defined until 1996
• predicted incubation period of 10-20 years
• vCJD epidemic peaked between 1999-2000, ~8 years after BSE epidemic peaked

Question 18

vCJD vs sCJD

Answer 18

• vCJD is distinguished from sCJD by the following features:
• type 4 PrPsc is unique to vCJD
• can be transmitted person to person by blood transfusion or ingestion of food contaminated with SE
• a considerably younger age of onset (29 versus 65 years)
• less rapid progression of illness (14 versus 5 months)
• vCJD has a peripheral pathogenesis
• differences in neuropathology

Question 19

vCJD problem in US?

Answer 19

• CDC has received reports of 3 confirmed cases in US residents- born in UK or Saudi Arabia
• a recent report indicated about 1 in 2000 people in UK carry the vCJD causing prion
• incubation 20-30 years
• uncertaintly exists about the possibility that human cases of vCJD that are silently incubating may be capable of producing secondary lateral

Question 20

New Targets for CJDs

Answer 20

• PrP13, a peptide that can break a beta-sheet conformation, was shown to reduce the protease resistance of PrPsc and to delay he onet the symptoms in transmission experiments in mice
• in murine scarpie model, anti-PrP monoclonal antibodies reduced PrPsc levels and prion infectivity
• mice treated with adenovirus vector platforms that express PrPc single chain fragment antibodies, and subsequently infected with PrPsc had delayed pathogenesis

Question 21

TSE precautions for healthcare workers

Answer 21

• employ universal precautions when handling blood and CSF
• highest risk from brain, spinal cord, and eye tissues
• scrupulously avoid contact with post-mortem tissues- don’t get it into cuts and scratches on your skin
• all precautions should be followed during autopsy and embalming

Question 22

Sterilization Procedures for Prions

Answer 22

• prions are highly resistant to conventional physical decontamination methods- resistant to disinfectants, heat, ultraviolet radiation, ionizing radiation, and formalin
• immerse in NaOH

Question 23

Prions and Alzheimer’s Disease

Answer 23

• Alzheimer’s disease is a form of progressive dementia
• polymorphism is the Prnp gene is a risk factor for AD
• PrPc binds to amyloid B peptides
• PrPc interaction with amyloid B peptides has been confirmed in patients with AD
• deletion of PrPc in mice prevented the development of AD
• mice injected with brain tissue from AD patients will developed disease- is misfolded amyloid B a prion?