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Flashcards in Prions Deck (23)

History of Transmissible Spongiform Encephalopathy

-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


Prion diseases

-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


Creutzfeldt- Jacob Disease

-the most frequent of human prion disease
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


sCJD symptoms and signs

-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)


What causes prion diseases

-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


PrPc Misfolding Causes Encephalopathy

-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


PrPsc classification

-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


Model for Prion Self Replication

-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


sCJD diagnosis

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

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


sCJD treatment and prognosis

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


sCJD Epidemiology

-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


Varient Creutzfeld Jacob Disease

-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


vCJD symptoms and signs

-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


vCJD diagnosis

-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


vCJD onset of disease

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


Time course of BSE in UK

-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


Incidence of BSE and vCJD in Great Britain

-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


vCJD vs sCJD

-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


vCJD problem in US?

-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


New Targets for CJDs

-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


TSE precautions for healthcare workers

-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


Sterilization Procedures for Prions

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


Prions and Alzheimer's Disease

-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?