Knowing the function of the protein that is linked to disease is important, you don’t want to disable something that is a component of another system. Similarly, if a gene variant confers resistance or reduced risk of a disease, you want to know why, because it could lead to possible intervention strategies for people who don’t carry that gene variant.

In Huntington’s the polyglutamine ends agglomerate together because they are not kept apart by a high enough ATP level. That clogs things up which causes â??stressâ? and the generic stress response is to lower NO and ATP still more. That is what causes the hypometabolism observed in all neurodegenerative diseases. There can simultaneously be observations of hypermetabolism, but that is late stage.

That may honestly be the first blog comment or posting I’ve seen that is actually interesting and thoughtful (much more so than the post here).

I hope you work in biology — it would make me feel much less negative about my field.

Who’d think that biology selects over ensembles and not over unique cases? That a population wide healthy response does not imply that every, or even most, individuals have healthy responses?

Reminds me of a journal club where I asked what the Huntington protein is for — other than to create Huntington’s disease. Apparently no one in my department had ever considered the possibility that a protein exists because it has a function that is selected for… and that this might be of interest when looking at the pathological case…

Sigh…

http://www.plosone.org/article/info:doi/10.1371/journal.pone.0012236

The whole paradigm that the genome researchers are working on is flawed. Yes, there are adverse effects like Alzheimer’s. Is there any evidence that the gene pathways are not working â??properlyâ?? By â??properlyâ?, I mean the way they evolved to work.

Are adverse effects like Alzheimer’s inextricably coupled to beneficial effects that the same gene pathways that produce? An example I like to use is anaphylaxis. Anaphylaxis can make eating a peanut lethal. Is anaphylaxis a â??bugâ?, or a â??featureâ?? It is clearly a highly complex integrated series of pathways that are invoked and do things in seconds and minutes when the appropriate stimulus hits the trigger point.

Evolution didn’t configure the immune system to stop all death, evolution configured evolution to minimize the sum of death and non-reproduction from all causes simultaneously. If bacteria get into your blood stream in â??the wildâ?, the only thing that has a chance of saving your life is a massively ginormous immune system response; like anaphylaxis. If anaphylaxis causes 5% deaths, but prevents 25% then it is a fabulously advantageous feature.

It isn’t that lethal anaphylaxis is good, but that an immune system that can support lethal anaphylaxis is superior to an immune system that can’t. It is just like being able to run yourself to death while running from a bear. Running yourself to death is not good, but a control system that lets you run yourself to death will allow escape from more bears than a control system that doesn’t.

In the context of Alzheimer’s, the major symptom is reduced metabolic activity. Reduced glucose consumption, reduced ATP. Those changes are global, over the whole brain. The whole brain has reduced metabolic activity. Every cell in the brain is working â??in syncâ? to achieve the same (but reduced) metabolism. How many pathways are involved in that reduced metabolic activity? One, five, ten or hundreds? How can hundreds of pathways â??go badâ? simultaneously in every cell in the brain? They can’t.

I don’t think that any pathways have â??gone badâ?. I see Alzheimer’s as good regulation around a bad setpoint. Metabolic activity has been turned down by the normal pathways working as they evolved to work. They just have a bad setpoint. A setpoint that is controlled by nitric oxide.

Low NO leads to low ATP and triggers ischemic preconditioning. Ischemic preconditioning can only be a transient state. If it goes on for too long, the cells will eventually die. I think that is what Alzheimer’s is. Ischemic preconditioning that has gone on for too long.