Presentation made April 8, 2016 at the live webinar hosted by Alzforum - http://www.alzforum.org/webinars/webinar-pathogenic-protein-spread-lets-think-again

1. NATURE REVIEWS NEUROSCIENCE

2. Objectives of our opinion piece
1. To attempt to make sense out of the huge amount of data from disparate studies.
2. Ask what other processes may help us understand the spatiotemporal progression of pathology?
4. Assuming “the spread hypothesis” to be true, consider:
(i) immediate practical consequences for medicine and research;
(ii) significance for current approaches to therapy.
5. Assess whether comparison of prion diseases and more common neurodegeneration disorders
provides mechanistic insight.
3. Suggest critical experiments.

3. Objectives of our opinion piece
1. To attempt to make sense out of the huge amount of disparate studies conducted in this area.
2. Ask what other processes may help us understand the spatiotemporal progression of pathology?
4. Assuming “the spread hypothesis” to be true, consider:
(i) immediate practical consequences for medicine and research;
(ii) significance for current approaches to therapy.
5. Assess whether comparison of prion diseases and more common neurodegeneration disorders
provides mechanistic insight.
3. Suggest critical experiments.

4. External/internal
stress
Pathogenic Spread model
NATURE REVIEWS NEUROSCIENCE

5. Selective Vulnerability model
NATURE REVIEWS NEUROSCIENCE

6. Selective Vulnerability model
NATURE REVIEWS NEUROSCIENCE

7. Time
Vulnerable neuron
Less Vulnerable neuron
NATURE REVIEWS NEUROSCIENCE

8. External/internal
stress
Less Vulnerable neuron
Hybrid model: Selective Vulnerability & Spread
NATURE REVIEWS NEUROSCIENCE

9. Objectives of our opinion piece
1. To attempt to make sense out of the huge amount of disparate studies conducted in this area.
2. Ask what other processes may help us understand the spatiotemporal progression of pathology?
4. Assuming “the spread hypothesis” to be true, consider:
(i) immediate practical consequences for medicine and research;
(ii) significance for current approaches to therapy.
5. Assess whether comparison of prion diseases and more common neurodegeneration disorders
provides mechanistic insight.
3. Suggest critical experiments.

10. There are 4 cell biological steps required for physical transfer of aggregates, and some of
these steps may be inconsistent with current principles of cell biology.
(1) Release from donor neurons.
(2) Aggregation (this could occur before or after point 1).
(3) Uptake into certain recipient neurons.
(4) Induction of aggregation in the recipient cells.

11. There are 4 cell biological steps required for physical transfer of aggregates, and some of
these steps may be inconsistent with current principles of cell biology.
NATURE REVIEWS NEUROSCIENCE

12. There are 4 cell biological steps required for physical transfer of aggregates, and some of
these steps may be inconsistent with current principles of cell biology.
NATURE REVIEWS NEUROSCIENCE
Tunneling nanotubes
Trans-synaptic transfer

13. 4
NATURE REVIEWS NEUROSCIENCE
Leakage due to synaptic degeneration

14. To date most studies have focused on histological lesions, but
future studies should focus on disease relevant dysfunction.

15. Objectives of our opinion piece
1. To attempt to make sense out of the huge amount of disparate studies conducted in this area.
2. Ask what other processes may better, or help understand the spatiotemporal progression of pathology?
4. Assuming “the spread hypothesis” to be true, consider:
(i) immediate practical consequences for medicine and research;
(ii) significance for current approaches to therapy.
5. Assess whether comparison of prion diseases and more common neurodegeneration disorders
provides mechanistic insight.
3. Suggest critical experiments.

16. Steady state
Oligomerization
Deposition
Oligomers
Fibrils
Monomer
5 5
5
4
3
Degradation
2
1
Many targets remain unchanged

17. New targets recommended by the Spread hypothesis
NATURE REVIEWS NEUROSCIENCE

18. Objectives of our opinion piece
1. To attempt to make sense out of the huge amount of disparate studies conducted in this area.
2. Ask what other processes may better, or help understand the spatiotemporal progression of pathology?
4. Assuming “the spread hypothesis” to be true, consider:
(i) immediate practical consequences for medicine and research;
(ii) significance for current approaches to therapy.
5. Assess whether comparison of prion diseases and more common neurodegeneration disorders
provides mechanistic insight.
3. Suggest critical experiments.

19. Potential for iatriogenic transmission
Dura mater transplants
- Preusser et al. 2006 J Neurol Neurosurg Psychiatry
- Frontzek et al. 2016 Swiss Med Wkly
- Kovacs et al. 2016 Act Neuropath
hGH studies
– Jaunmuktane et al. 2015 Nature
CAREFUL EPIDEMIOLOGICAL ANALYSIS.
SYSTEMATIC PRIMATE STUDIES INCLUDING FUNCTIONAL READOUTS.

20. Objectives of our opinion piece
1. To attempt to make sense out of the huge amount of disparate studies conducted in this area.
2. Ask what other processes may better, or help understand the spatiotemporal progression of pathology?
4. Assuming “the spread hypothesis” to be true, consider:
(i) immediate practical consequences for medicine and research;
(ii) significance for current approaches to therapy.
5. Assess whether comparison of prion diseases and more common neurodegeneration disorders
provides mechanistic insight.
3. Suggest critical experiments.

21. Less is known about the mechanisms of prion disease than many appreciate
1. The connection between transmissibility and toxicity is not well understood.
2. How infectivity spreads between neurons, and whether it involves trans-
synaptic transfer is not well understood.
3. Not all prion diseases have significant aggregates, and not all aggregates in
prion diseases are amyloid.
4. The cell biology of PrP which is normally present inside cells, on the plasma
membrane and can be secreted is distinct from largely cytoplasmic tau or α-
synuclein.
5. It has proved difficult to produce synthetic prions, but relatively easy to seed
tau and α-synuclein, and with the latter exhibiting no apparent species
barriers.

22. The biggest challenge in neurodegeneration?
To identify and characterize the primary neurotoxins that
mediate disease.