Lecture neurodegenerative disorders 5: prion and prion-like

Question 1

Prion diseases can be sporadic, genetic or acquired. Name examples of prion diseases that belong to these causes.

Answer 1

• Sporadic → Creutzfeldt-Jakob disease (CJD)
• Genetic → familial Creutzfeldt-Jakob disease (fCJD), Gerstmann-Sträussler-Scheinker syndrome (GSS), Fatal familial insomnia (sFI).
• Acquired → Kuru, iatrogenic Creutzfeldt-Jakob disease (iCJD) or variant Creutzfeldt-Jakob disease (vCJD)

Question 2

What’s the typical pathology of prion disease?

Answer 2

• Holes formed in tissue → spongiformic changes in grey matter
• Large vacuoles
• Perivacuolar PrP deposits

Question 3

What are prions?

Answer 3

Prions are infectious protein particles that can transmit a misfolded protein state to another protein.

Question 4

What causes the sponge form in brain tissue in prion disease?

Answer 4

Accumulation of these perivacuolar PrP deposits

Question 5

What are transmissable spongioform encephalopathies (TSEs)?

Answer 5

A group of progressive and fatal conditions that are associated with prions and affect the brain and nervous system of many animals (e.g. humans, cattle and sheep).

Question 6

What are sources/causes of acquired prion diseases or transmissable spongioform encephalopathies (TSEs)?

Answer 6

• Organ transplant
• Drugs from human origin
• Brain surgery
• Disease diagnosis
• Clinical trials
• Blood banks and plasma products
• Food industry

Question 7

What kind of mutations in aggregating proteins like PrP cause human neurodegenerative disease, like prion disease?

Answer 7

Missense mutations in the PrP protein

Question 8

Name the disease stages for fatal familial insomnia (FFI), also desribe how long these stages can last.

Answer 8

1. Increasing insomnia, which results in panick attacks, paranoia and phobias (lasts 4 months)
2. Hallucinations and panick attacks (lasts 5 months)
3. Complete inability to sleep is followed by rapid loss of weight (lasts 3 months)
4. Dementia, during which the patient becomes unresponsive or mute (lasts up to 6 months).

Question 9

Where in the brain are prion deposits found in fatal familial insomnia patients?

Answer 9

In the thalamus, the brain area where sleep is regulated.

Question 10

In the picture, normal sleep stages are depicted. What’s different in the sleep cycle of patients of fatal familial insomnia?

Answer 10

Their sleep doesn’t go beyond stage 1.

Question 11

What was found in the Fore people in New Guinea?

Answer 11

A heterozygous protective allele (G127V) in the PrP gene for prion disease. This allele was found in the Fore people after the Kuru epidemic.

Question 12

The heterozygous protective allele (G127V) was then tested for its protectiveness in mouse models. What did they do and what was the result?

Answer 12

They used a wildtype mice (i.e. control) and compared it with a mouse that was injected with the protective allele. They then injected prion proteins in both mice and compared the mice for formation of aggregates. They saw that in the control mouse, aggregates were formed. This wasn’t the case for the experimental mouse with the protective allel. So this proves the protective function of the allele against prion diseases.

Question 13

What disease has shown to have prion-like mechanisms?

Answer 13

In Parkinson’s disease: if healthy dopaminergic neurons (from stem cells or iPS) are transplanted into someone with Parkinson’s disease to treat the disease, it’s seen that 14 years after the transplant Lewy bodies have aggregated in these dopaminergic neurons. This is something you would not expect, since the tissue was healthy/normal when it was transplanted into the brain. It indicates that the graft cells have obtained the disease from the host cells. So, there’s seeding of endogenous aggregation in Parkinson’s.

Question 14

In the picture: prion like behaviour explained (from soluble proteins to insoluble filaments). Just study.

Answer 14

Ok

Question 15

How can you study prion like behaviour of α-synuclein?

Answer 15

By intracerebral injecting (inoculating) pathological α-synuclein in the brain of mice and monitor the spreading.

Question 16

So, pathological α-synuclein was injected in a mousebrain. What was the conclusion of this study in regard to spreading of α-synuclein?

Answer 16

There was progressive spreading of α-synuclein, as can be seen in the picture.

Question 17

What else was seen when pathological α-synuclein was injected in a mousebrain?

Answer 17

That intracerebral inoculation of pathological α-synuclein activates astroglia

Question 18

What other aggregates have prion-like mechanisms? What’s different to this aggregate compared to α-synuclein pathological aggregates?

Answer 18

Tau aggregates also have prion-like spreading. It transverses/spreads from one part of the brain to the other part of the brain via synaptic connection that exist. The difference with α-synuclein is that tau spreads via connectivity, not proximity.

Question 19

Describe the spreading of tau (pathology) in Alzheimer’s disease.

Answer 19

• Tau pathology start in the transentorhinal cortex → prodromal stage.
• It then spreads to the hippocampus and temporal cortex (limbic system) → early-moderate stage
• And then spreads to all the isocortical areas → moderate-late stage

Question 20

How can you study tau spreading (and confirm the spreading observed before)?

Answer 20

By generating a mutant tau (P301L tau) and expressing the mutant in the entorhinal cortex of a mouse. Due to the mutation, tau will misfold and aggregate.

Question 21

How did they ensure that tau was only expressed in the entorhinal cortex during the study of tau spreading with P301L mutant tau?

Answer 21

By using a promotor sequence that is only expressed in the entorhinal cortex. This way you can confirm that if tau pathology spreads, it really originates from the entorhinal cortex and not e.g. from the hippocampus.

Question 22

What was the conclusion of the P301L mutant tau study that studied tau spreading in the brain?

Answer 22

The mutant tau aggregates in the entorhinal cortex. Over time, the aggregates become more dense and it was seen that the aggregates had spread to the dentate gyrus. After a while, tau spreading was also seen in the hippocampus. This indicates that tau is spread from the entorhinal cortex to the hippocampus. This is confirmed by the fact that P301L mutant tau is made sure to be only expressed in the entorhinal cortex and that the mRNA is not detected in the hippocampus.

Question 23

Are there other diseases, besides Parkinson’s and Alzheimer’s disease, that have pathological spreading?

Answer 23

Yes, besides α-synuclein in Parkinson’s and Tau in Alzheimer’s, it is also found for TDP-43 in ALS and Aβ in Alzheimer’s.

Question 24

Depicted in the picture is prion like behaviour or seeding of aggregation. How can you simulate and study this in regard to tau spreading?

Answer 24

By labelling normal intracellular tau with GFP and adding extracellular tau fibrils labeled red to this. This causes uptake of extracellular tau fibrils, which induces intracellular tau to aggregate.

Question 25

There are three potential mechanisms for transcellular propagation of protein misfolding. Two are important in local spreading and one is important in network spreading. Name these.

Answer 25

1. Cell with aggregates → cell death and release of aggregates → uptake of aggregate by viable cell (local spread)
2. Cell with aggregates → exocytosis of aggregate → aggregae uptake by another cell (local spread)
3. Aggregate in presynaptic cell body/neuron → release of aggregate by synaptic interaction and release → uptake of aggregate by postsynaptic cell (network spread)

Question 26

What is a new approach and hypothesis of the cause of Alzheimer’s?

Answer 26

Since there is prion-like spreading and recruitment of endogenous tau, it might be possible that Alzheimer’s is an infectious disease.

Question 27

Now that we know and understand the spreading of aggregates, we might be able to block the spreading. How can this be done?

Answer 27

Blocking the spread of aggregation → when an aggregate is released from a cell, it will be taken up by an adjacent antibody instead of the next cell.