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CJD damage mechanism


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I'm curious if anyone knows specifically how PrPsc causes cellular damage and death in Creutzfeldt Jakob Disease. I gather it has something to do with myelinated axons. What specifically is it about the misfolding and accumulation of PrP that causes cells to die? I realize this is a rather hypothetical area but I'll settle for the prevaling theory.


Prion, this should be right up your alley.

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In theory it's right up my alley but I don't think anyone knows exactly! Some mechanisms have been excluded though. It's not due to loss of normal prion protein (PrP) function because PrP-knockout mice don't have neurodegeneration. It's not simply due to the presence of PrPSc as people have tried putting bits of infected brain into the brain of PrP knockout mice and no damage is done to surrounding tissue even if the PrPSc migrates into it.


It's quite possible an intermediate in the folding pathway between normal PrPC and PrPSc is neurotoxic, and the PrPSc build up is not relevant. In support of this, animals and people have died of prion disease with little or no PrPSc. This has also been considered as a possibiliy in other amyloid disease like Alzheimers and Huntington's - actual amyloid fibrils don't seem to be neurotoxic. It's even been suggested that formation of amyloid may be a protective cell mechanism to get rid of damaging misfolded protein.


Another theory that I like that could go along with the previous idea is that cell death could happen when the cell's protein degradation machinery gets overloaded by all the abnormal protein (as PrPSc is resistant to proteases) and bursts open, releasing all the digestive enzymes. Then the death of that cell would release all the contents to infect the neighbouring cells, and so on. This matches the spongy/holey patterns in the brain that occur. Also mice show the same neurodegeneration when protein degradation is inhibited.


There have been some speculations that abnormal cleavage of the protein could make a peptide that can insert into membranes in a damaging way and be neurotoxic that way. Some research groups are passionate about the possibility that abnormal PrP could bind metal ions in an abnormal way and cause oxidative damage, but other groups are still sceptical about that.


The reason the CNS neurons are selectively damaged is because that's where PrP is most highly expressed. Though it's expressed at low levels everywhere and it's now known that the blood of people with variant CJD is potentially infectious.


So that's where things are at the moment! The hot topic is PrP folding, trying to work out what causes it to misfold and what forms are toxic to what cells...lots of cell culture etc. I left that field a couple of years ago though. Got fed up of containment labs :)

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