3 ms·

Could a cure be to stop proteosynthesis of the prion-protein? https://blogs.scientificamerican.com/artful-amoeba/prions-are-forever/ https://blogs.scientificam

by fsloth 5y ago

Could a cure be to stop proteosynthesis of the prion-protein? https://blogs.scientificamerican.com/artful-amoeba/prions-are-forever/ https://blogs.scientificamerican.com/artful-amoeba/prions-ar... "This protein, in its healthy, properly-folded state, is, if not trivial, relatively unimportant. Its complete loss is certainly not catastrophic." I have no idea how to block proteosynthesis of a single protein in humans, maybe more biologically attuned HN:ners can comment what it would mean (I'm totally clueless of cellular biology).

jhgb 5y ago
It seems to me that in an adult, it may already be too late. How would you remove the existing protein?
- im3w1l 5y ago
  Maybe it would degrade after some time, or be cleaned up by the body. At worst it should stop the disease progression.
- subroutine 5y ago
  Proteins have a half life of ~24 hours. CJD has an incubation period of roughly 10 years. If de novo PrP synthesis was somehow halted, the likelihood of developing CJD would drop to zero. On the other hand whatever job PrP was doing will also cease getting done, and its downstream pathways will be disrupted. So there are likely consequences. Now if you could totally shut down PrP synthesis for like a week, then turn it back on, that might work. In theory this is possible using a tet-expression system [1], but I've never worked with a tet system that wasn't leaky. The only sure way would be to KO PrP genes from all cells, then CRISPR it back in a week later. Oh, and I'm talking about cells in a culture dish; this strategy would never work in an adult human. [1] https://www.jax.org/news-and-insights/2015/april/introduction-to-tet-expression-systems https://www.jax.org/news-and-insights/2015/april/introductio...
  - jhgb 5y ago
    > Proteins have a half life of ~24 hours. All of them? I admit that I'm not a biologist, so that's new to me, but this would seem to put our bodies under immense stress if we had to replace half of all our proteins every day. If the average human body has 10 kg of proteins, this would mean the necessity of synthesizing 5 kg per day to prevent your death. Or is this specifically about PrP? If it's true that it doesn't last long, then perhaps stopping its synthesis would be a viable option. Does the misfolded PrP have a different half-life?
    - subroutine 5y ago
      There is certainly a large standard deviation on that 24 hour average. Some proteins might last a few days. But we are talking on the order of days vs. the disease which takes on the order of years to manifest. Anyway I assume that the disease manifests as a result of bad PrP accumulation (much like how tau and Abeta protein accumulation eventually results in Alzheimer's disease; in fact Abeta has been described as having "prion like" properties regarding how Abeta clusters beget more clusters). So as soon as you shut down PrP synthesis, I doubt CJD could manifest, even if the current PrP in your body was immortal.
nlitened 5y ago
> "This protein, in its healthy, properly-folded state, is, if not trivial, relatively unimportant. Its complete loss is certainly not catastrophic." If I at my age know anything about how real world works, absence of evidence is not an evidence of absence, and I can bet that this will turn out to be complete bullshit, and it will get known in the future that this protein is important.

by fsloth 5y ago

jhgb 5y ago

It seems to me that in an adult, it may already be too late. How would you remove the existing protein?

im3w1l 5y ago
Maybe it would degrade after some time, or be cleaned up by the body. At worst it should stop the disease progression.
subroutine 5y ago
Proteins have a half life of ~24 hours. CJD has an incubation period of roughly 10 years. If de novo PrP synthesis was somehow halted, the likelihood of developing CJD would drop to zero. On the other hand whatever job PrP was doing will also cease getting done, and its downstream pathways will be disrupted. So there are likely consequences. Now if you could totally shut down PrP synthesis for like a week, then turn it back on, that might work. In theory this is possible using a tet-expression system [1], but I've never worked with a tet system that wasn't leaky. The only sure way would be to KO PrP genes from all cells, then CRISPR it back in a week later. Oh, and I'm talking about cells in a culture dish; this strategy would never work in an adult human. [1] https://www.jax.org/news-and-insights/2015/april/introduction-to-tet-expression-systems https://www.jax.org/news-and-insights/2015/april/introductio...
- jhgb 5y ago
  > Proteins have a half life of ~24 hours. All of them? I admit that I'm not a biologist, so that's new to me, but this would seem to put our bodies under immense stress if we had to replace half of all our proteins every day. If the average human body has 10 kg of proteins, this would mean the necessity of synthesizing 5 kg per day to prevent your death. Or is this specifically about PrP? If it's true that it doesn't last long, then perhaps stopping its synthesis would be a viable option. Does the misfolded PrP have a different half-life?
  - subroutine 5y ago
    There is certainly a large standard deviation on that 24 hour average. Some proteins might last a few days. But we are talking on the order of days vs. the disease which takes on the order of years to manifest. Anyway I assume that the disease manifests as a result of bad PrP accumulation (much like how tau and Abeta protein accumulation eventually results in Alzheimer's disease; in fact Abeta has been described as having "prion like" properties regarding how Abeta clusters beget more clusters). So as soon as you shut down PrP synthesis, I doubt CJD could manifest, even if the current PrP in your body was immortal.

nlitened 5y ago

> "This protein, in its healthy, properly-folded state, is, if not trivial, relatively unimportant. Its complete loss is certainly not catastrophic." If I at my age know anything about how real world works, absence of evidence is not an evidence of absence, and I can bet that this will turn out to be complete bullshit, and it will get known in the future that this protein is important.