Prions and Transmissible Spongiform Encephalopathies Flashcards
Identification of spongiform encephalopathy
first in papa New Guinea at Kuru epidemic; disease was being spread by endocanibalism
Kuru shares similarities with
CJD (rare human neurodegenerative disease) and scrapie; CNS degeneration with areas of brain becoming vacuolated or spongy, extensive deposition of fibrils or plaques
CJD
rare human neurodegenerative disorder; onset at 60; 10-15% cases are inherited; shown to have infectious nature in 1968 when cerebral innoculations from CJD patients performed on non-human primates; was transmitted through human growth hormone
Kuru experiment on chimps
saw signs 18-21 months after cerebral inoculation in non-human primates
Koch’s postulation of causation
- causal agent should be found in animals suffering from dx not healthy animals
- when isolated from dx animal and inoculated into susceptible animal dx with characteristic symptoms and clinical outcome should result
- should be possible to reisolate same causal agent from experimental animals to demonstrate chain of transmission
Identification prion protein
used Syrian hamster bioassay; brain extractions to purify infectious agent;PrP identified as protease resistant protein uniquely present in scrapie brain
prion
proteinaceous infectious particle that lacks nucleic acid passed on via epigenetic inheritance
epigenetic inheritence
infectious agents passed form mother cell to daughter cell with no dependence on RNA or DNA; violated previously accepted rule that inheritance and infection had to require RNA or DNA
Prion protein encoded by
PRNP gene (=PrPc) (proteins come from genes genes are transcripts from RNA)
PRNP and prion disease
PRNP= PrPc is delted in mice they are completely resistant to prion infection, if PRNP transgene reintroduced then they are once again susceptible; over expression PrP in old wild type mouse leads to spongiform dx; PRNP essential component of infectious prion
PrPc and PrPsc
AA sequence of both are identical and there are no post translational modifications the difference is in the way they fold, PrPc has alpha helices and is globular , PrPsc has beta sheets
PrPsc conformation and disease
PrPsc has beta sheets instead of alpha helices and is not globular like PrPc; B sheets can form protease resistant, insoluble fibrils by hydrogen bonding between B sheets; accumulation of fibrils in plaques can cause cell death and neurodegeneration
amyloid
protein accumulation (plaque formed by fibrils); amyloid is the abnormal staining deposit name in path exam
why is PrPc needed to develop prion dx
PrPsc induces PrPc to chance conformation bc of hydrophobic AAs and converts it into PrPsc and accumulates into fibrils its v rare to have globular PrPc to conformational change without PrPc causing it
heterodimer
PrPsc beta sheet with PrPc globular protein
homodimer
2 PrPsc beta sheet structures together
Biological roles of prion domain conversion
1 example is spider web, goes from alpha helices to beta sheets between storage and web making
human diseases similar to CJD
GSS syndorme and fatal family insomnia
polymorphysims of PRNP
CJD- cerebral cortex
FFI- thalamus
Kuru, Gss- cerebellum
BSE- brainstem
All related to prion gene but effect diff regions of brain and have different symptoms because of small subtile AA changes
Prion strains phenotypic differences
incubation times, histopathological lesion profiles, and specific neuronal target areas; phenotypic traits typically persist upon serial transmission
prion broad deffinition
protein that infinitely propagates an altered form of itself without DNA or RNA; propagation of protein is transmissible
Psi
yeast prion; when cells have Psi they’re white when they don’t they’re red if treated with unfolding agent they can go from white to red bc cells given a chance to fix misfolded proteins; indicates we may be able to see if chaperones can help with misfiled proteins in people with TSE
what is happening at the molecular level dominant epigenetic inheritance
normal proteins can produce folding intermediates with sticky surface which acts as template to bind and trap other partially unfolded proteins newly synthesized proteins can get trapped in the aggregate; aggregates are passed to successive generations of cells through cytoplasm to propagate disease
other neurodegenerative conditions associated with spongiform like changes in CNS
Prion dx, alzheimers, Parkinson’s, frontotemporal dimensia, Picks dx, progressive supra nuclear palsy, ALS, Huntinton’s, spinocerebellar ataxias
These are all due to aberrant proteins proteinneuropathies that eventually lead to cell toxicity and degeneration
Alzheimer’s
insoluble plaques of amyloid and neurofibrally tangles; genetic predispositions (specific mutations associated with familial forms of early onset alzheimers (increased beta amyloid); amyloid accumulation in brain associated with polymorphisms
Huntington’s disease
codes for polyglutamine which leads to repeater of sticky glutamine (coded for by CAG) that leads to prion like properties that leads to aggregation and neurotoxicity; this is genetic disorder
mouse model huntingtons
can turn hd gene on and off; turn off to stop production of protein halts disease progression and can reverse aggregate formation
polyglutamine tract aggregation yeast
causes cell death in yeast model (toxic single cell aggregation)
aggregation phenotype depends on (in PolyQ aggregation)
depends on there being another prion protein present in the cell (Huntington’s requires presence of a prion); prions induce aggregation of other proteins/ prions
adult onset neurodegeneration
neurodegenerative disease have long latency; mechanism of proteinopathy type diseases similar in principle to what we know about prion dxs; complex interplay of contributing factors to developing protein aggregates (if excellent proteins chaperones may not have same level of aggregates)
alzheimers dx propigation
propigated in prion like fashion with cerebral extractions
Kuru survivors
found to have higher levels of AA at one position that effects spongiform and prion susceptibilities mice were resistant to prion dx when inoculated with this
Kuru surviviors relation to public health
related bc of vCJD and BSE need to known about prion susceptibility if a TSE comes back in epidemic form
outstanding questions from TSE research
why do we have PrPc, why does PrPsc effect brain/ NS, what is prion uptake/ distribution method between cells, molecular structures of prion oligomers and amyloid fibers, relationship between protein fibrils and neurotoxicity, cell mechanisms to deal with protein aggregation, how can prions affect other proteins aggregating, what determines interspecies susceptiblity
CLassifications of transmissible spongiform encephalopathies
acquired- horizontal transmission; CJD, Kuru, CWD, BSE, vCJD, TME, feline spongiform encephalopathy, iatrogenic transmission
Familial- vertical transmission, inherited from cell to cell and via predisposing mutations transmitted from parent to offspring (CJD, FFI, GSS, BSE, Scrapie)
Sporadic- idiopathic prion disease can arise spontaneously (CJD)
