Prion Disease

Question 1

Clinical manifestations of prion disease

Answer 1

Dementia
Ataxia
Insomnia
Paraplegia
Parasthesias
Deviant behaviour

Question 2

Prions diseases may manifest as…

Answer 2

Infectious, genetic, or sporadic disorders. No other group of illnesses with a single cause has such a wide spectrum of clinical manifestations

Question 3

Prion diseases results from…

Answer 3

The accumulation of PrPsc which has a substantially different conformation from that of its normal precursor PrPc
PrPsc can have a variety of conformations, each of which seems to be associated with a specific disease

Question 4

Prions are devoid of…

Answer 4

The only known example of infectious pathogens that are devoid of nucleic acid

Question 5

Scrapie protein and template directed misfolding

Answer 5

The mutant (Scrapie form of the Prion) binds to normal prion protein molecules
in nerve cells and causes them to permanently misfold in a process called
“template-directed misfolding”. The process is then repeated by the newly
misfolded molecule leading to massive accumulations of toxic protein. The
mutant prions may then be released to “seed” the process in nearby normal
cells.

Question 6

Prions reproduce by

Answer 6

Refuting normal cellular prion protein PrPc and timulating its conversion to the disease causing scrapie isoform PrPSc though a process called template directed misfolding

Question 7

What is a major feature that distinguishes prions from viruses

Answer 7

PrPsc is encoded by a chromosomal gene

Question 8

Limited Proteolytic of PrPsc produces

Answer 8

Smaller protease-resistant molecule of approx 142 amino acids, designated PrP27-30 which polymerises into amyloid

Question 9

The regular function of PrPc is

Answer 9

Uncertain as PrPc knockout mice show no obvious abnormalities

Question 10

Describe the central mechanism of prion-mediated cell death

Answer 10

Initiated by prion-mediated activation and perversion of the
normally protective “Unfolded Protein Response” (UPR).
 The PERK kinase arm of the UPR results in the transient shutdown
of protein translation, through phosphorylation of the a-subunit
of eukaryotic translation initiation factor, eIF2.
 Accumulation of prion protein causes irreversible phosphorylation
of eIF2 (to yield eIF2α-P) with persistent translational repression
of global protein synthesis
 Failure of protein synthesis rapidly leads to loss of synaptic
function and cell death. (Nature 2012; 485:507 – 11)
 Prions liberated from infected or dying cells are seeded via uptake
by normal cells in a vicious-cycle of spreading pathology.

Question 11

Examples of prion disease affecting humans

Answer 11

Creutzfeldt-Jakob
Fatal familial insomnia
Sporadic fatal insomnia

Question 12

What does histology look like in prion disease

Answer 12

Widespread ‘spongiform’ degeneration due to loss of neurons in cerebral cortex from a patient with sporadic CJD
Specific staining for GFAP reveals astrogliosis in same disease

Question 13

Evidence for prion-like propagation in other ND-diseases

Answer 13

1)Recent evidence suggests that amyloids from non-prion neurodegenerative
diseases not only have similar structures but may have similar properties
2)Soluble Amyloid- β Seeds Are Potent Inducers of Cerebral β-Amyloid
Deposition
3)Inoculation of brain homogenates containing Aβ aggregates into susceptible
transgenic mice accelerated Aβ deposition, suggesting that Aβ aggregates
are capable of self-propagation and hence might act as prions (prionoids).
4)Inoculation of misfolded α-synuclein from Lewy Bodies of human brain,
promote formation of Lewy Body pathology in host neurons of recipient
animals.
5)Transplants of foetal dopaminergic neurons in Parkinson’s patients
developed α-synuclein +ve Lewy bodies.
6)Aggregates containing both mutant and wild type SOD-1 have been found in
brain tissue from individuals with familial ALS.

Question 14

What is seeded aggregation

Answer 14

Seeded aggregation is the process whereby misfolded proteins recruit and initiate
template-directed misfolding of the native protein to form new aggregates. Such
toxic proteins are called PRIONOIDS to distinguish them from Prions, as although
proven in mice, there is as yet little evidence that they are transmissible from one
individual to another in humans. However, the prevalence of amyloid-β pathology
in the brains of people with iatrogenic CJD (40%) , compared to sporadic CJD (2%)
suggests seeding of Aβ in addition to the primary causative agent, the V2 strain of
human prion protein.

Question 15

Prionoid disease spread in NDD system analysis

Answer 15

1) In addition to the above evidence, several recent
systems-based analysis studies of fMRI data have
concluded that the evidence supports a
“transmural spread” model of disease progression
in NDDs.
2)These conclusions were also predicted from
systems analysis of the “functional connectome”
determined in healthy brains.
(see Refs in slide notes)