Prion disease
What are prion diseases?
Prion disease are rare progressive neurodegenerative disorders that affect both
humans and animals.
The most known prion disease is called scrapie (sheep,goat), the name scrapie
derives from the fact that diseased animals scrape their skin by rubbing against
fences or other objects. This is because of itching. Scrapie is not transmissible to
human beings this is because of a phenomenon that is called species barrier. In
earlier days because of the bad practise of feeding cattle with material contaminated
with scrapie, it was possible for human beings who ingested bovine to contract the
disease. Because these cattle were fed with meat and bones from sheep’s and goat
that had scrapie, the possibility was to overcome the species barrier and for human
beings to be infected. The bovine spongiform encephalopathy disease in animals is
called Creutzfeldt-Jakob disease in humans.
Prion diseases: neuropathology
A human in severe stage prion disease has an increase in empty spaces in the cortex.
The more severe the disease the more empty spaces. This is why it is called brain
spongiform degeneration, because it looks like a sponge, there is the presence of
large spaces or vacuoles in the tissue. There is also gliosis.
There is the deposit of pathological prions, these prions are misfolded aggregated
proteins
Prions are infectious, the incubation period may be years.
The clinical phase is very quick, it is typically rapidly progressive (weeks to months).
The clinical symptoms: behavioural abnormalities, motor dysfunction, cognitive
impairment, ataxia, insomnia (depending on the prion and the species affected.) it
depends on the prion that affects that specific species but also on the species.
Prion diseases are fatal diseases so there is no cure for them.
There is also no sign of an immune response to a foreign infectious agent.
Prion concept: experimental evidence:
The brain extracts of diseased animals were able to transmit the disease.
The treatment of these extracts with nucleases or UV light (both nucleases and UV
light are able to destroy nucleic acids, all the DNA and RNA) does not prevent
transmission. This means that the transmission was not linked to DNA or RNA.
However, the treatment of the same extract with very powerful protein denaturants
was able to reduce infectivity.
PrPc
PrPc is the physiological form of the prion protein.
PrPc is a cell surface protein that is expressed in a variety of different tissues and
organs, and it is highly expressed in the CNS and PNS.
It is highly conserved in mammals, this means that there is an important
physiological role for that specific protein.
It is encoded by the PRNP gene.
The mature PrPC protein is attached to the outer cell membrane by a GPI anchor.
, PrPc function
Scientists found that if PrPc is not present then there were alterations in synaptic
transmission and plasticity, in memory formation and stabilization of sleep and
circadian rhythm. Insomnia is a symptom of prion disease. Neuronal excitability,
calcium homeostasis, neurite outgrowth. Toxicity elicited by oligomeric species looks
like if PrPc is not there, there is a protection from A beta toxic species in Alzheimer’s
disease. Somehow there is a connection, it looks like PrPc can somehow regulate
the sensitivity to A beta toxicity.
Neuroprotection, peripheral myelin maintenance.
If PrPc is not there, there is an age-dependant demyelinating neuropathy.
PrPc has lots of functions that are important for the normal CNS and PNS
functioning.
PrPC & PrPSC.
What happens when PrPc becomes PrPSC.
The structure of PrPC and it is made from 3 alpha helices.
There is a small part of the protein that is organised in terms of secondary structure
into Beta sheet. This protein is detergent soluble, it is protease sensitive, and it is
associated to the membrane.
When this protein becomes PrPsc, there is a big change in the secondary structure of
the protein. The big parts of the protein are organised into beta sheet
conformations.
This PrPsc is detergent insoluble, it is partially protease resistant, and it is abnormally
folded.
It is the same protein but with a completely different secondary structure.
FEATURE PrPc (normal isoform) PRPSC (scrapie isoform)
Present in normal brain Yes no
Present in scrapie-infected yes yes
brain
Covalent modifications GPI anchor, Asn- linked Probably identical to PrPc
polysaccharides, single
intramolecular disulfide
bond
Soluble in mild detergents yes No
Effect of protease Hydrolysed to small Protease resistant C-
peptides terminal portion of variable
length.
Conformation
Secondary structure: local 40% alpha-helical, little beta 30% beta sheet and 20%
conformation of the sheet. alpha helix.
polypeptide chain
Tertiary structure: overall 3 alpha helical regions, Cryo-electron microscopy,
fold of the polypeptide. unstructured N-terminus. X-ray fiber diffraction, and a
variety of other approaches
defined the structure of
What are prion diseases?
Prion disease are rare progressive neurodegenerative disorders that affect both
humans and animals.
The most known prion disease is called scrapie (sheep,goat), the name scrapie
derives from the fact that diseased animals scrape their skin by rubbing against
fences or other objects. This is because of itching. Scrapie is not transmissible to
human beings this is because of a phenomenon that is called species barrier. In
earlier days because of the bad practise of feeding cattle with material contaminated
with scrapie, it was possible for human beings who ingested bovine to contract the
disease. Because these cattle were fed with meat and bones from sheep’s and goat
that had scrapie, the possibility was to overcome the species barrier and for human
beings to be infected. The bovine spongiform encephalopathy disease in animals is
called Creutzfeldt-Jakob disease in humans.
Prion diseases: neuropathology
A human in severe stage prion disease has an increase in empty spaces in the cortex.
The more severe the disease the more empty spaces. This is why it is called brain
spongiform degeneration, because it looks like a sponge, there is the presence of
large spaces or vacuoles in the tissue. There is also gliosis.
There is the deposit of pathological prions, these prions are misfolded aggregated
proteins
Prions are infectious, the incubation period may be years.
The clinical phase is very quick, it is typically rapidly progressive (weeks to months).
The clinical symptoms: behavioural abnormalities, motor dysfunction, cognitive
impairment, ataxia, insomnia (depending on the prion and the species affected.) it
depends on the prion that affects that specific species but also on the species.
Prion diseases are fatal diseases so there is no cure for them.
There is also no sign of an immune response to a foreign infectious agent.
Prion concept: experimental evidence:
The brain extracts of diseased animals were able to transmit the disease.
The treatment of these extracts with nucleases or UV light (both nucleases and UV
light are able to destroy nucleic acids, all the DNA and RNA) does not prevent
transmission. This means that the transmission was not linked to DNA or RNA.
However, the treatment of the same extract with very powerful protein denaturants
was able to reduce infectivity.
PrPc
PrPc is the physiological form of the prion protein.
PrPc is a cell surface protein that is expressed in a variety of different tissues and
organs, and it is highly expressed in the CNS and PNS.
It is highly conserved in mammals, this means that there is an important
physiological role for that specific protein.
It is encoded by the PRNP gene.
The mature PrPC protein is attached to the outer cell membrane by a GPI anchor.
, PrPc function
Scientists found that if PrPc is not present then there were alterations in synaptic
transmission and plasticity, in memory formation and stabilization of sleep and
circadian rhythm. Insomnia is a symptom of prion disease. Neuronal excitability,
calcium homeostasis, neurite outgrowth. Toxicity elicited by oligomeric species looks
like if PrPc is not there, there is a protection from A beta toxic species in Alzheimer’s
disease. Somehow there is a connection, it looks like PrPc can somehow regulate
the sensitivity to A beta toxicity.
Neuroprotection, peripheral myelin maintenance.
If PrPc is not there, there is an age-dependant demyelinating neuropathy.
PrPc has lots of functions that are important for the normal CNS and PNS
functioning.
PrPC & PrPSC.
What happens when PrPc becomes PrPSC.
The structure of PrPC and it is made from 3 alpha helices.
There is a small part of the protein that is organised in terms of secondary structure
into Beta sheet. This protein is detergent soluble, it is protease sensitive, and it is
associated to the membrane.
When this protein becomes PrPsc, there is a big change in the secondary structure of
the protein. The big parts of the protein are organised into beta sheet
conformations.
This PrPsc is detergent insoluble, it is partially protease resistant, and it is abnormally
folded.
It is the same protein but with a completely different secondary structure.
FEATURE PrPc (normal isoform) PRPSC (scrapie isoform)
Present in normal brain Yes no
Present in scrapie-infected yes yes
brain
Covalent modifications GPI anchor, Asn- linked Probably identical to PrPc
polysaccharides, single
intramolecular disulfide
bond
Soluble in mild detergents yes No
Effect of protease Hydrolysed to small Protease resistant C-
peptides terminal portion of variable
length.
Conformation
Secondary structure: local 40% alpha-helical, little beta 30% beta sheet and 20%
conformation of the sheet. alpha helix.
polypeptide chain
Tertiary structure: overall 3 alpha helical regions, Cryo-electron microscopy,
fold of the polypeptide. unstructured N-terminus. X-ray fiber diffraction, and a
variety of other approaches
defined the structure of
