Read with caution!
This post was written during early stages of trying to understand a complex scientific problem, and we didn't get everything right. The original author no longer endorses the content of this post. It is being left online for historical reasons, but read at your own risk.
Some of the potential areas of discussion are:
I. Mechanism of mutation effects
A. Protein level
eg what are the effects of the mutation polymorphism combination on the protein
What are the lessons from the other mutant PRNPs?
B. Cell level
Pathways that lead to PRNP folding in general
Pathways that lead to mutant PRNP folding/misfolding in specific
Pathways that lead to differential protein synthesis
Pathways that lead to differential protein degradation
C. Organ/System level
Is there a true premorbid/early disturbance in sleep cycle?
Are there any SQUID/PET/NMR modes that detect activity or tissue state
Mechanisms for biomarker generation and therapeutic agent effects
Discovering measures to assess modifier/therapeutic effects in short term
mouse model / patient
Are there factors/agents that alter any of the above?
Effects from other genetic variations?
Could one use variant genetic backgrounds or genetic screens to test for this?
Mouse model over variant genetics (especially with protein-based transmission?)
Drosophila model a possibility for suppressor screen?
Any similarity to glutamine repeat expansion mechanisms?
Effects of aging? Continuous or accelerative?
Effects of hormones, drugs, or medications?
II. Screening platforms
Given any of that, are there any clues to guide/prioritize experimental
plan for screening?
What are the potential kinds of screening platforms for evaluating
A. Mouse model
Purified protein injection
B. Cell model
Cells from the mouse
Cells from people
C. Purified protein model
Mutant vs. wildtype protein
D. Small molecule docking
drug library binding assays and technologies
III. What are potential classes of candidate therapeutic agents?
A. Therapeutics targeting the mutant
B. Therapeutics that more generally address or modify
protein folding machinery
protein degradation machinery
Other host pathways
Systemic / localized inflammation
Effects of circadian patterns
Growth control (protein synthesis and turnover)
IV. Very simple agents/and strategies to consider having at least a potentially helpful role
Anti-growth agents, eg: promoting autophagy
Mild pathway modulators, eg: vitamin D, E, flavins, curcumin etc (lessons from mother’s course relative to others?)
Stronger pathway effectors, eg: Sirolomus, Everolimus, EGFR inhibitors
Bone marrow transplantation to suppress disease progression via glial cell replacement?
Making stem cells from patients?
Best platforms for evaluating potentially therapeutic oligos to suppress mutant protein synthesis? Where exactly in the cell is the protein synthesized? Is there trans-cellular protein trafficking and turnover?