How Now Mad Cow? Introduction to Prion Disease and Function shp – Neurobiology of Development and Disease
How Now Mad Cow?
to Prion Disease and Function
SHP – Neurobiology of Development and Disease
Invariably fatal, chronic neurodegenerative disease.
First reported in England, France and Germany in the 19th century.
Long period of incubation (2-5 years).
rub their coats against trees
, suffer ataxia, convulsions,
, anorexia, and eventually death.
Death usually occurs within 1-6 months.
Discovered by Carleton Gajdusek in the 1950’s and 60’s among the South Fore people of New Guinea.
Transmitted through ritual mortuary cannibalism where deceased individuals were consumed by their relatives to honor them.
Shirley Lindenbaum reported that maternal kin would remove the arms and feet of the corpse, strip the muscles
and remove the internal organs
, including the brain.
Between 1957 and 1968, over 1,100 South Fore succumbed to kuru. Early on it affected mostly women (80% vs men) but later also affected elderly and children at high rates as well.
Symptoms of Kuru
– myoclonus, unsteadiness of stance/gait/hands/eyes, dysarthria,
slurring of speech
, tremor, uncoordination of lower extremities that progresses upwards.
– victim can no longer walk, severe tremors, ataxia,
shock-like muscle jerks
, emotional lability, inappropriate laughter and extreme depression, cognitive decline.
intensifying symptoms above
, urinary and fecal incontinence, dysphagia (difficulty swallowing), lapse into coma, and lose control of breathing.
Transmissibility was unintentially demonstrated by inoculation of a Scottish sheep herd with a vaccine extract prepared from formalin treated brain of a scrapie-infected animal.
Within 2 yrs, 10% of the flock contracted scrapie.
Gajdusek notes similarity in brain pathology between Kuru and scrapie. He goes on to inject chimpanzees with Kuru brain extracts, after which they exhibit TSE pathology.
Investigators follow up by showing transmissibility to animals of CJD,
, and GSS.
In 1967, Alper and his group report the extreme resistance of scrapie infectivity to UV light and ionizing radiation.
They previously isolate this activity to 200kD, eliminating the role of even viruses as the vehicle.
In 1967, JS Griffith proposes three possibilities for these findings:
1) agent is a protein that turns on its own transcription
2) agent is a variant protein form that can corrupt the native form of protein to its state via oligomerization.
3) agent is an antibody that stimulates its own production.
Progression of BSE
1986: First case of BSE discovered in a cow that was fed livestock feed produced from a sheep that died of scrapie.
Dr. Richard Lacey annouces that scrapie and BSE are the same disease and that “this beef was in the meat supply”.
British government dismisses Lacey and cuts his research funding. They announce that scrapie renderings are still an acceptable form of livestock feed.
Progression of BSE (cont)
1987: 700 BSE infected cows are reported in Great Britain.
1988: 7,000 infected cows. Law is passed declaring sheep rendering illegal.
1992: 36,000 infected livestock reported.
1994: 150,000 infected livestock reported and is identified in half of British cattle herds.
Crossing the line…..
In 1996, a new form of CJD is discovered in the UK, termed variant CJD (vCJD).
Linked with consumption of BSE-contaminated beef.
the symptoms of classic CJD
, except the median age of death is 28 (contrasting with 68) and feature psychiatric and sensory symptoms with neurologic effects occuring later.
Secondary routes of transmission (iatrogenic CJD)
Dura and corneal transplants.
Being operated on with surgical tools used on a CJD patient.
EEG depth probes contaminated by previous patients.
Molecular prion characteristics
Usually rich in polar amino acids such as glutamine or asparagine.
Computational structure prediction suggests poor secondary structure preference.
The domain is dispensable for the function of the protein.
The protein can exist in soluble or aggregated form.
Non-Mendelian genetic element that is transmitted by cytoplasmic mixing.
Prion phenotype can be reversed by denaturation and arises again spontaneously at low frequency.
Expression of endogenous gene is required to propagate prion form.
Overexpression of gene increased spontaneous conversion to the prion form.
Protein can exist in two states (like PrP): soluble/protease-sensitive and insoluble/protease-resistant.
Conversion process can be reconstructed in vitro by conversion of native conformation to the prion form by progressive dilution.
Prion domain is modular and can be transferred to other genes.
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