While ATP may help to solubilize proteins, I don't find it surprising the cells under question have very high ATP concentrations. I take issue with this statement:
> In addition to being an energy source for biological reactions, for which micromolar concentrations are sufficient, we propose that millimolar concentrations of ATP may act to keep proteins soluble. This may in part explain why ATP is maintained in such high concentrations in cells.
Sure it's important for neurons to prevent amyloid-beta from aggregating, but we can explain why neurons have a super high (mM) ATP concentration for two other good reasons:
1. Unlike other cells, neurons conduct electrical signals. Every time a neuron fires it opens channels that allow sodium and potassium to flow through the membrane. Then, it needs to get those ions back across the membrane so the neuron can keep functioning. To do this neurons make prodigious use of Na/K-ATPase pumps, that exchange intracellular Na for extracellular K, against an electrochemical gradient. This is active transport that requires tons of ATP. In a typical animal cell active transport is a relatively small (~1/10th) portion of cellular energy expenditure compared to neurons (~7/10th).
2. ATP is used in actin filament polymerization. Each molecule of filamentous actin is coupled to an ATP molecule, and actin is found in neurons at mM concentrations. Actin is a major structural protein in cells, and plays a particularly important role in neurons. Actin helps create filopodial protrusions; if you compare a neuron to another type of cell you can immediately tell it's a protrusion machine. Even these protrusions (axons and dendrites) have protrusions (neurites and dendritic spines) that are constantly reorganizing to allow for structural plasticity among the brain's neural network connections. One of my dissertation projects was to simulate actin activity in neurons; for anyone's interested, here are some pretty neat visuals of this...
Guessing this is a major reason that "big" brains are extremely rare. There's strong selective pressure against such an energy hungry organ and most of benefits (ooh, we can discuss issues on HN) don't accrue until much later. ;-)
For broader context, this might be used to help explain the well known link between the age-related decline in mitochondrial function (and consequence lowered production rate of ATP) and the age-related development of aggregates such as amyloids and tau. Aggregates are age-related, but one needs explanations as to why that is the case. Other proximate causes include declining cellular garbage collection mechanisms, aggregation of other proteins (protein A spurs aggregation of protein B), failure of mechanical clearance via peristaltic channels, and so forth. It's never just one thing.
Like many lines of research manage to achieve, this finding adds a little more emphasis to the need to restore mitochondrial function in the old. Clearing damaged mitochondria, delivering replacement mitochondria to cells, allotopic expression of mitochondrial genes, and so forth.
>"Aggregates are age-related, but one needs explanations as to why that is the case."
I don't think there is much mystery here. As cells divide they accumulate (genetic, and other types of) errors. One thing that happens is proteins/peptides are more likely to end up in their most thermodynamically stable state, since it requires constant maintenance to avoid it.
I don't think that necessarily explains how an offspring resets all of that. By that same logic, there should be a limit to how many generations of human there are.
Apparently there are about 7 million oocytes created per generation[1], which could be done in 23 divisions: 2^23 = 8,388,608
So first, it doesn't require that many divisions per generation of human. Second, there are "errors" that get passed on to the offspring. Third, a lot of selection goes on so that only fertilized eggs without huge issues will eventually be born.
Right, but it would seem like many such strategies could be applied to somatic cells. And we also know that there are complex organisms that don't meaningfully age.
You're dismissing the idea of (1) proving the "obvious" solution or disproving it via data, and you're ignoring the "how". "There are errors" doesn't say where they are errors, and how those errors translate into behavior. If the hypothesis in the source article is help up by more data, that is actually a huge deal, not just confirming something we already knew.
The review I shared contains many ideas along these lines. Basically the AA sequences seem to be selected to disfavor aggregation, so most mutations should increase formation:
>"Many of the characteristics of proteins that enable the
avoidance of aggregation, and amyloid formation in particular,
are encoded by their amino acid sequences116. The
elucidation of this code has enabled the identification of
factors that determine the intrinsic aggregation propensity
of these molecules117–119. Hence, it has been realized
that globular proteins fold into structures that sequester
aggregation-prone regions in their interior; in addition,
typical features of the folding process, such as very high
cooperativity, generate considerable kinetic barriers to the
conversion of folded proteins into aggregation-prone species50,120.
Furthermore, specific patterns of residues, such
as alternating hydrophobic–hydrophilic stretches50,121, that
tend to favour the amyloid state are commonly selected
against during evolution119,121,122 or are otherwise neutralized
by the insertion of highly aggregation-resistant
residues, which are known as ‘gatekeepers’
(REFS 50,123)."
Really I doubt in the end there will be any disease not associated with amyloid/aggregate formation.
So given that neurons almost never divide (1), and other cell types like skin cells divide every few hours (2), based on your formulation how do we explain that we never find A-beta plaques in skin cells?
----
1. It was thought that adult neurons didn't divided at all until like 1998; now we know some new neurons are produced from progenitor sources at very low rates.
2. 30,000 to 40,000 skin cells are produced every minute.
Would it be encouraging to see if amyloid plaques dissolve in a concentrated aqueous solution of ATP? (Sorry if nonsensical. I am approaching the topic as a layman.)
Had a different response here before but this quote from the article suggests maybe!
"ATP kept proteins in boiled egg white from aggregating."
It also appears the concentrations they're talking about are quite reasonable (10mM or so).
That said, once an aggregate is formed you usually need pretty heroic methods to solubilize it. Much stronger detergents and denaturants at higher must be used, and in those cases you run into other problems.
After solubilizing the aggregate, you have to fold the individual proteins back up. But now you have to do it in an environment where you 1.) a molecule that keeps the protein unfolded and 2.) a ton of other unfolded proteins around. You could slowly get rid of 1.) by dialysis or something similar. But when you have a bunch of unfolded proteins hanging around together, you almost always get aggregates.
In practice, it's quite unlikely that ATP concentrations high enough to unfold an aggregate wouldn't unfold all sorts of other things. This would also mean the stuff you need to keep the rest of the cell working... so from a practical perspective this is unlikely to work.
> In addition to being an energy source for biological reactions, for which micromolar concentrations are sufficient, we propose that millimolar concentrations of ATP may act to keep proteins soluble. This may in part explain why ATP is maintained in such high concentrations in cells.
Sure it's important for neurons to prevent amyloid-beta from aggregating, but we can explain why neurons have a super high (mM) ATP concentration for two other good reasons:
1. Unlike other cells, neurons conduct electrical signals. Every time a neuron fires it opens channels that allow sodium and potassium to flow through the membrane. Then, it needs to get those ions back across the membrane so the neuron can keep functioning. To do this neurons make prodigious use of Na/K-ATPase pumps, that exchange intracellular Na for extracellular K, against an electrochemical gradient. This is active transport that requires tons of ATP. In a typical animal cell active transport is a relatively small (~1/10th) portion of cellular energy expenditure compared to neurons (~7/10th).
2. ATP is used in actin filament polymerization. Each molecule of filamentous actin is coupled to an ATP molecule, and actin is found in neurons at mM concentrations. Actin is a major structural protein in cells, and plays a particularly important role in neurons. Actin helps create filopodial protrusions; if you compare a neuron to another type of cell you can immediately tell it's a protrusion machine. Even these protrusions (axons and dendrites) have protrusions (neurites and dendritic spines) that are constantly reorganizing to allow for structural plasticity among the brain's neural network connections. One of my dissertation projects was to simulate actin activity in neurons; for anyone's interested, here are some pretty neat visuals of this...
Actin polymerization to create a dendritic spine: https://youtu.be/JH-hGjzhEFQ
Small segment of a dendrite with surface receptor diffusion: https://www.youtube.com/embed/6ZNnBGgea0Y
Creating dendritic meshes in python: https://youtu.be/tDKUU0SqbSA