Prions, Mad Cow Disease and Creutzfeldt-Jakob Disease (9/9)

Liu (Lecture 26)

what are transmissible spongiform encephalopathies?

fatal neurodegenerative disease caused by prions

long incubation time before symptoms show up

Scrapie the sheep

prototypic prion disease

“scrapie” describes infected sheep that constantly scraped objects while their brains were being degenerated

What is Bovine Spongiform Encephalopathy (BSE)? What is the incubation time? What 2 distinct features of this disease?

Mad Cow disease that results from feeding cattle with and bone meal contaminated from scrapie sheep

incubation time ~5 yrs: most cattle did not manifest disease bc they are sacrificed between 2-3 yrs

Cows are unable to stand, holes/spongiform in brain tissue

Who discovered human creutzfeldt-Jakob Disease (CJD)? What does it look like? Who does it affect the most?

first described by Hans Herhard Creutzfeldt and Alfons Maria Jakob

sponge-like lesions in brain, amyloid fibrils are misfolded prions that accumulate in the brain

most common human prion disease: affects ages 45-75, mostly 60-65

Is there a diagnostic test for CJD? What do you do first? How can you confirm CJD?

there is no single diagnostic test for CJD

first, rule out treatable forms of dementia such as encephalitis or chronic meningitis

confirmation: brain biopsy or autopsy

describe a brain biopsy. Why is it strongly discouraged?

remove small piece of tissue from brain so that ic an be examined by the neurologist

discouraged bc correct diagnosis doesn’t help the pt, unless its needed to rule out a treatable disorder

What are the 3 major categories of CJD? How common is each category?

85% sporadic CJD

10-15% hereditary (familial) CJD: 100% penetrance, carriers will eventually develop disease

<1% acquired CJD

What are some symptoms of CJD?

altered behavior, dementia, memory loss, impaired senses, delirium, premature senility, uncontrollable muscle contractions

Acquired CJD

acquired from human or from BSE

What is the difference between CJD and vCJD (variant from BSE)

CJD:

• median age at death: 68

• median duration: 4-5 mo

• S&S: dementia, early neurological signs

vCJD:

• median age at death: 28

• median duration: 13-14mo

• S&S: prominent pscyhiatric/behavioral symptoms, delayed neurological signs

What is Human Kuru?

infection through ritualistic cannibalism

endemic disease prevalent among New Guinea highland Natives

What are some features of transmissible spongiform encephalopathies

resistant to chemicals, ionizing radiation, heat

do not present virus morphology in electron microscopy

not assoc w foreign nucleic acid isolated from infected host cells

proteinaceous, filterable

multiplies slowly in cell culture, no cytopathic fx

do not elicity inflamm rxn or antibody formation in host (nonimmunogenic)

responsible for plaques and abnormal fibers forming in brain

transmission: intimate contact with infected tissues and secretions

define prions.

causative agent of spongiform encephalopathies

proteinaceous infectious particles that are devoid of nucleic acid and composed of a modified form of the prion protein

what are prions designated as? Where is it present?

PrP

present in normal healthy people (aka PRP^c)

diseased form of prion: PrP^sc “scrapie”

Location: on the cell surface through glycosylphosphatidyl inositol (GPI) moiety

What is human Prp encoded by?

single copy of PrP gene on chromosome 20

other species have a single copy PrP gene in genome

prion gene from 40 different species has been sequenced except

chickens

other than chickens, prion protein from other species is similar to human prion protein

before the discovery of prions, what was thought to be the cause of TSE?

slow virus

associated with the fact that incubation is very long.

How does prion protein sequence identity across species relate to the prion transmission barrier?

• Prion diseases transmit more easily between species whose PrP proteins are highly similar.

• Human PrP shares:

  • 99% identity with chimpanzee PrP → very low transmission barrier.

  • 92% with sheep, 90% with cow, 90% with mouse PrP → moderate barrier.

  • 41% with chicken PrP → very high barrier; transmission unlikely.

PrP^c knockout mice

apparently healthy mice that are resistant to prion disease and unable to replciate prions

describe the moa of prion diseases

conformation change: PrPc is unfolded and refolded into PrPsc — alpha-helical sturcture converted into beta-sheet

accompanied by physico-chemical property changes > eventual deposition of amyloid fibrils > tangles the brain

simplified moa of prion diseases

PrPsc can induce PrPc to be converted into PrPsc

PrPsc conformation enciphers prion diversity

What type of mutations do inherited and sporadic CJD results from?

Inherited CJD results from germline mutations in the prion gene

sporadic CJD can results from somatic mutation of the prion gene

whether CJD can be resulted from spontaneous conversion of PrPc into Prpsc in the absence of a mutation remains to be determined

Epidemiology of BSE and vCJD. What did epidemiologicaland and experimental studies show?

1994 in teenagers and young adults eventually labeled as vCJD occurred in the Great Britain

Studies show: vCJD is result of prions being transmitted from cattle with BSE to humans through consumption of contaminated beef products

Gerstmann-Sträussler-Scheinker (GSS) Syndrome

rare, familial, fatal neurodegenerative disease that affects pts from 20-60 yrs

incidence: 1 to 10 per 100 million

what type of mutation does GSS have?

point mutation in prion gene that leads to deposition of Prp amyloid

change in codon 102 from proline to leucine

what are some symptoms of GSS?

developing dysarthria (difficulty speaking) and cerebellar ataxia (unsteadiness) and then the progressive

Is there a cure or treatment for GSS?

NO, it has a longer clinical course compared to other prion diseases, pts rarely survive longer than 5 yrs

what type of mutation occurs to create fatal familial insomnia?

genetic form is caused by dual mutations in prion gene:

• substituted aspartic acid by asparagine at codon 178

• methionine at the position 129

what is fatal familial insomnia? Are there any distinct triggers?

very rare prion disease due to selective degeneration of the dorsal medial nuclei of the thalamus, which controls sleep

• results in reduced sleep and evenutally the inability to sleep

• sporadic and genetic forms

• autosomal dominant disease

It strikes during middle age and results in death. It has no apparent trigger, patients last up to 3 yrs

SEQ the 4 stages of fatal familial insomnia

1. onset: panic attacks, unfounded phobias that last 4 mo

2. severe insomnia, worsening panic attacks and hallucinations that last 5 mo

3. complete insomnia, rapid wt loss that last 3 mo

4. dementia, unresponsiveness that last 6 mo

FFI is eventually fatal

What is the history of FFI? Who is Silvano and Michael Corke

Italian man in Venice 1765. Family secret for generations

stopped being a secret with Silvano who went to University of Blognea and filmed his final months with FFI

• donated brain to research > structure in thalamus was spongy and degraded

Michael Corke: in Chicago had trouble sleeping, died after not sleeping for 6 mo

• DNA sequencing found 2 mutations in prion gene for FFI

Species Barrier (prion related issue)

prolongation of incubation period when prions are transferred form one speciesto another

on second passage of prions in same species, incubation decreases than remain constant on subsequent passage

how prion proteins pass the BBB?

not completely understood

1. partially bypass BBB

• retrograde spread through thoracic spine peripheral nerves

• involvement of immune cells

2. directly cross BBB

• PrPsc oligomers can cross BBB without disruption