4 ms·

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 p

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.

JumpCrisscross 9y ago
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.)
- deleted 9y ago
  [deleted]
- entee 9y ago
  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.
nonbel 9y ago
>"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. http://www.nature.com/nrm/journal/v15/n6/full/nrm3810.html http://www.nature.com/nrm/journal/v15/n6/full/nrm3810.html
- ergothus 9y ago
  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.
  - nonbel 9y ago
    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.
- subroutine 9y ago

JumpCrisscross 9y ago

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.)

deleted 9y ago
[deleted]
entee 9y ago
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.

nonbel 9y ago

>"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. http://www.nature.com/nrm/journal/v15/n6/full/nrm3810.html http://www.nature.com/nrm/journal/v15/n6/full/nrm3810.html

ergothus 9y ago
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.
- nonbel 9y ago
  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.
subroutine 9y ago