6 ms·

Mucins keep the brain safe and could guard against ageing

192 points by walterbell 2y ago

Trasmatta 2y ago
...in mice.
- owlninja 2y ago
  We have to start somewhere.
  - account-5 2y ago
    True but "in mice" in the title would save a lot of time.
    - SapporoChris 2y ago
      I would settle for a non-click bait title.
- the__alchemist 2y ago
  Thought-terminating Cliche.
- alt227 2y ago
  Surprising how many times this exact comment is posted on HN these days. Arent all human treatments tested on mice first?
  - elif 2y ago
    it's not surprising when you consider the title says "the brain" and not "mice brains" journalists are ruining our understanding of reality by sensationally misleading people with headlines in search of engagement.
    - walterbell 2y ago
      https://news.ycombinator.com/item?id=43237205 https://news.ycombinator.com/item?id=43237205 > a recently approved new drug for schizophrenia suggests that a connection between mucins and brain function in humans is more than speculative
walterbell 2y ago
explainer: https://archive.is/vMfmZ https://archive.is/vMfmZ open access paper: http://doi.org/10.1038/s41586-025-08589-9 http://doi.org/10.1038/s41586-025-08589-9 > We demonstrate that we can improve BBB function and reduce neuroinflammation and cognitive deficits in aged mice by restoring core 1 mucin-type O-glycans to the brain endothelium using adeno-associated viruses. Cumulatively, our findings provide a detailed compositional and structural mapping of the ageing brain endothelial glycocalyx layer and reveal important consequences of ageing- and disease-associated glycocalyx dysregulation on BBB integrity and brain health.
- ein0p 2y ago
  This isn't my field, so apologies if I'm off-base, but this seems to make viruses do what they couldn't do previously, and moreover, target the brain. Wouldn't that qualify as GoF research? And if so, after millions dead and trillions lost, how prudent is it to conduct this kind of research?
  - Sniffnoy 2y ago
    "Gain-of-function" doesn't refer to adding literally any function to a virus, it refers to making it more virulent or transmissible -- that's why lots of people are so against it, because the cost-benefit ratio seems so obviously lopsided. Adding unrelated functions to viruses and using them as vectors isn't included in that, both in that it has lots more uses (some vaccines are made this way, for instance) and much lower downside risk (viruses used as vectors are often rendered unable to replicate, so the risk of them spreading at all is small). > Wouldn't that qualify as GoF research? And if so, after millions dead and trillions lost, how prudent is it to conduct this kind of research? While this isn't the main point, I feel like I should point out that (if I'm understanding you correctly) there seems to be something fundamentally wrong with your reasoning here. Whether or not it's a good idea to conduct this particular research is a matter of the facts of this particular case. How you categorize it doesn't change that. Learning what is or is not considered "gain of function" should have zero effect on your opinion here! Here's a good essay on this topic: https://www.lesswrong.com/posts/TyQSMmoJpRG3HBv5S/cleaning-up-the-worst-argument-essay https://www.lesswrong.com/posts/TyQSMmoJpRG3HBv5S/cleaning-u...
hirenj 2y ago
This area is very much in my wheelhouse (both the biosynthetic process, and functions of mucins). They’re a pretty interesting biomolecule, present in all animals (slightly different molecules in other branches of life). It kind of surprises me that such a low fold-change in core1 synthase yields such a huge change in glycocalyx. Everything we know about this enzyme says it is an absolute rocket on substrates, so I can’t really see this process being enzyme-limited. There might be other (mouse specific) things going on here that this is scratching the surface on.
- menzoic 2y ago
  I’m also surprised that a slight change in C1GalT1 expression has such a big effect on the glycocalyx. That enzyme is notoriously high-capacity, so you’d think it runs at near-saturating levels most of the time. My hunch is that something else in the pathway is hitting a bottleneck, possibly a chaperone like Cosmc that’s needed for proper enzyme folding, or maybe there’s some substrate competition with parallel glycosylation pathways. Once that bottleneck is reached, even a small shift can have an outsized impact on final glycan structures. In mice specifically, there might be unique regulatory quirks that amplify this effect, and you end up with a dramatic change in the mucins even though the enzyme itself seems too powerful to be the limiting step.
  - hirenj 2y ago
    Yes, something along these lines, and maybe the other pathways as the most interesting possibility. I don’t know if there any reports of sTn in older mice, but that would be pretty wild.
- randall 2y ago
  thanks for doing work on this and thanks for commenting on it on hn!!
- FollowingTheDao 2y ago
  Copper and calcium seem to stimulate some mucins.
polskibus 2y ago
What can we eat/do to boost this barrier?
- greggsy 2y ago
  This is basically the first thing asked by the layman when these types of observations emerge. The replies will almost certainly be regurgitated into a misleading article, which in turn will kick off a damaging trend.
  - bloomingeek 2y ago
    Isn't it time for a serious conversation about the wonderful health benefits of ivermectin? (:
    - giardini 2y ago
      It's effective against ticks, fleas and mites (cause scabies) and more. Easy to apply (pour on skin/fur at back of neck). Get dosage right: instructions are on the box/container. My cat has a much less scratchy life thanks to ivermectin.
    - unsupp0rted 2y ago
      Should ivermectin be removed from this list? https://en.wikipedia.org/wiki/WHO_Model_List_of_Essential_Medicines https://en.wikipedia.org/wiki/WHO_Model_List_of_Essential_Me...
  - deadbabe 2y ago
    Eat chlorophyll and spirulina to boost brain slime!
  - chung8123 2y ago
    While you are right about the misleading articles that will likely come from this, we do need to pay attention to what we eat so it is a reasonable question and one that should be investigated.
- hirenj 2y ago
FollowingTheDao 2y ago
Humans have several Mucins genes, each affecting a different part of the body. For example, MUC2 effects the intestines. Many of these mucin enyzmes need copper and calcium. Basically, it is mucus. These re also glycosylated proteins, which means proteins with sugar in layman terms. There is no need for gene editing. We have some clues. N-acetylcysteine (NAC) is a mucolytic agent with known effects on mucus viscosity and clearance.More here: https://stanmed.stanford.edu/neurotransmission-connection-mucus-hypersecretion/ https://stanmed.stanford.edu/neurotransmission-connection-mu...
- amelius 2y ago
  https://pubmed.ncbi.nlm.nih.gov/35975308/ https://pubmed.ncbi.nlm.nih.gov/35975308/ How could NAC help here, if it reduces mucus?
- hirenj 2y ago
  Mucins aren't enzymes (as far as we know!), and the gut mucins are a bit different from those found on the endothelium, largely because they have different functions. The gut (and generally mucous epithelial) mucus is there for (amongst other things) clearing and maintaining a microbiome. Endothelial glycocalyx probably has some other mucin proteins, but also likely lots of mucin-like proteins, and the set of functions of these are much less clear.
  - FollowingTheDao 2y ago
    The enzyme MUC(1-whatever) makes mucin. https://www.uniprot.org/uniprotkb?query=mucin&facets=model_organism%3A9606 https://www.uniprot.org/uniprotkb?query=mucin&facets=model_o...
    - hirenj 2y ago
      I think what you mean is the MUC1-20 (ish, numbering is a bit sloppy but hopefully we can clean it up in near future) genes encode for mucins, that are synthesised on a ribosome, threaded into ER, shuffled off into the Golgi and then enzymatically modified by the enzymes encoded by the genes GALNT2, 7 & 10 (at least). There are a further 20-30 ish enzymes that can modify the mucins as they are traversing the Golgi, and depending on the cell type, it can get packaged into vesicles (alongside calcium) for secretion. So, they meet a lot of enzymes along the way, but harbour no catalytic activity themselves (as far as we know!).
kyleblarson 2y ago
Does the spelling of the word "ageing" look strange to anyone else? I looked it up and it appears to be acceptable, but why not "pageing", "cageing" etc?
- deleted 2y ago
  [deleted]
- deleted 2y ago
  [deleted]
napierzaza 2y ago
[dead]
elif 2y ago
IN MICE**
- LoganDark 2y ago
  All statements relating to biology should be assumed to be about mice unless stated otherwise.
bregav 2y ago
Some are noting that this is "in mice", but a recently approved new drug for schizophrenia suggests that a connection between mucins and brain function in humans is more than speculative: https://en.wikipedia.org/wiki/Xanomeline/trospium_chloride https://en.wikipedia.org/wiki/Xanomeline/trospium_chloride Brand name Cobenfy, this drug is a combination of a muscarinic agonist and a muscarinic antagonist. Notably its therapeutic component was initially developed as an alzheimer's treatment, and IIRC showed positive results in the few trials that were performed in the 90's before the drug was abandoned due to side effects (until now).
walterbell 2y ago
Stanford explainer, https://news.ycombinator.com/item?id=43233003 https://news.ycombinator.com/item?id=43233003 > What if a critical piece of the puzzle of brain aging has been hiding in plain sight? While neuroscience has long focused on proteins and DNA, a team of Stanford researchers dared to shift their gaze to sugars – specifically the complex sugar chains that cover all our cells like chain mail.. Shi’s project was the first to investigate how age affects its sugary armor – the glycocalyx.. “Modulating glycans has a major effect on the brain – both negatively in aging, when these sugars are lost, and positively, when they are restored,” Shi says. “This opens an entirely new avenue for treating brain aging and related diseases.”

192 points by walterbell 2y ago

Trasmatta 2y ago

...in mice.

owlninja 2y ago
We have to start somewhere.
- account-5 2y ago
  True but "in mice" in the title would save a lot of time.
  - SapporoChris 2y ago
    I would settle for a non-click bait title.
the__alchemist 2y ago
Thought-terminating Cliche.
alt227 2y ago
Surprising how many times this exact comment is posted on HN these days. Arent all human treatments tested on mice first?
- elif 2y ago
  it's not surprising when you consider the title says "the brain" and not "mice brains" journalists are ruining our understanding of reality by sensationally misleading people with headlines in search of engagement.
  - walterbell 2y ago
    https://news.ycombinator.com/item?id=43237205 https://news.ycombinator.com/item?id=43237205 > a recently approved new drug for schizophrenia suggests that a connection between mucins and brain function in humans is more than speculative

walterbell 2y ago

explainer: https://archive.is/vMfmZ https://archive.is/vMfmZ open access paper: http://doi.org/10.1038/s41586-025-08589-9 http://doi.org/10.1038/s41586-025-08589-9 > We demonstrate that we can improve BBB function and reduce neuroinflammation and cognitive deficits in aged mice by restoring core 1 mucin-type O-glycans to the brain endothelium using adeno-associated viruses. Cumulatively, our findings provide a detailed compositional and structural mapping of the ageing brain endothelial glycocalyx layer and reveal important consequences of ageing- and disease-associated glycocalyx dysregulation on BBB integrity and brain health.

ein0p 2y ago
This isn't my field, so apologies if I'm off-base, but this seems to make viruses do what they couldn't do previously, and moreover, target the brain. Wouldn't that qualify as GoF research? And if so, after millions dead and trillions lost, how prudent is it to conduct this kind of research?
- Sniffnoy 2y ago
  "Gain-of-function" doesn't refer to adding literally any function to a virus, it refers to making it more virulent or transmissible -- that's why lots of people are so against it, because the cost-benefit ratio seems so obviously lopsided. Adding unrelated functions to viruses and using them as vectors isn't included in that, both in that it has lots more uses (some vaccines are made this way, for instance) and much lower downside risk (viruses used as vectors are often rendered unable to replicate, so the risk of them spreading at all is small). > Wouldn't that qualify as GoF research? And if so, after millions dead and trillions lost, how prudent is it to conduct this kind of research? While this isn't the main point, I feel like I should point out that (if I'm understanding you correctly) there seems to be something fundamentally wrong with your reasoning here. Whether or not it's a good idea to conduct this particular research is a matter of the facts of this particular case. How you categorize it doesn't change that. Learning what is or is not considered "gain of function" should have zero effect on your opinion here! Here's a good essay on this topic: https://www.lesswrong.com/posts/TyQSMmoJpRG3HBv5S/cleaning-up-the-worst-argument-essay https://www.lesswrong.com/posts/TyQSMmoJpRG3HBv5S/cleaning-u...

hirenj 2y ago

This area is very much in my wheelhouse (both the biosynthetic process, and functions of mucins). They’re a pretty interesting biomolecule, present in all animals (slightly different molecules in other branches of life). It kind of surprises me that such a low fold-change in core1 synthase yields such a huge change in glycocalyx. Everything we know about this enzyme says it is an absolute rocket on substrates, so I can’t really see this process being enzyme-limited. There might be other (mouse specific) things going on here that this is scratching the surface on.

menzoic 2y ago
I’m also surprised that a slight change in C1GalT1 expression has such a big effect on the glycocalyx. That enzyme is notoriously high-capacity, so you’d think it runs at near-saturating levels most of the time. My hunch is that something else in the pathway is hitting a bottleneck, possibly a chaperone like Cosmc that’s needed for proper enzyme folding, or maybe there’s some substrate competition with parallel glycosylation pathways. Once that bottleneck is reached, even a small shift can have an outsized impact on final glycan structures. In mice specifically, there might be unique regulatory quirks that amplify this effect, and you end up with a dramatic change in the mucins even though the enzyme itself seems too powerful to be the limiting step.
- hirenj 2y ago
  Yes, something along these lines, and maybe the other pathways as the most interesting possibility. I don’t know if there any reports of sTn in older mice, but that would be pretty wild.
randall 2y ago
thanks for doing work on this and thanks for commenting on it on hn!!
FollowingTheDao 2y ago
Copper and calcium seem to stimulate some mucins.

polskibus 2y ago

What can we eat/do to boost this barrier?

greggsy 2y ago
This is basically the first thing asked by the layman when these types of observations emerge. The replies will almost certainly be regurgitated into a misleading article, which in turn will kick off a damaging trend.
- bloomingeek 2y ago
  Isn't it time for a serious conversation about the wonderful health benefits of ivermectin? (:
  - giardini 2y ago
    It's effective against ticks, fleas and mites (cause scabies) and more. Easy to apply (pour on skin/fur at back of neck). Get dosage right: instructions are on the box/container. My cat has a much less scratchy life thanks to ivermectin.
  - unsupp0rted 2y ago
    Should ivermectin be removed from this list? https://en.wikipedia.org/wiki/WHO_Model_List_of_Essential_Medicines https://en.wikipedia.org/wiki/WHO_Model_List_of_Essential_Me...
- deadbabe 2y ago
  Eat chlorophyll and spirulina to boost brain slime!
- chung8123 2y ago
  While you are right about the misleading articles that will likely come from this, we do need to pay attention to what we eat so it is a reasonable question and one that should be investigated.
hirenj 2y ago

FollowingTheDao 2y ago

Humans have several Mucins genes, each affecting a different part of the body. For example, MUC2 effects the intestines. Many of these mucin enyzmes need copper and calcium. Basically, it is mucus. These re also glycosylated proteins, which means proteins with sugar in layman terms. There is no need for gene editing. We have some clues. N-acetylcysteine (NAC) is a mucolytic agent with known effects on mucus viscosity and clearance.More here: https://stanmed.stanford.edu/neurotransmission-connection-mucus-hypersecretion/ https://stanmed.stanford.edu/neurotransmission-connection-mu...

amelius 2y ago
https://pubmed.ncbi.nlm.nih.gov/35975308/ https://pubmed.ncbi.nlm.nih.gov/35975308/ How could NAC help here, if it reduces mucus?
hirenj 2y ago
Mucins aren't enzymes (as far as we know!), and the gut mucins are a bit different from those found on the endothelium, largely because they have different functions. The gut (and generally mucous epithelial) mucus is there for (amongst other things) clearing and maintaining a microbiome. Endothelial glycocalyx probably has some other mucin proteins, but also likely lots of mucin-like proteins, and the set of functions of these are much less clear.
- FollowingTheDao 2y ago
  The enzyme MUC(1-whatever) makes mucin. https://www.uniprot.org/uniprotkb?query=mucin&facets=model_organism%3A9606 https://www.uniprot.org/uniprotkb?query=mucin&facets=model_o...
  - hirenj 2y ago
    I think what you mean is the MUC1-20 (ish, numbering is a bit sloppy but hopefully we can clean it up in near future) genes encode for mucins, that are synthesised on a ribosome, threaded into ER, shuffled off into the Golgi and then enzymatically modified by the enzymes encoded by the genes GALNT2, 7 & 10 (at least). There are a further 20-30 ish enzymes that can modify the mucins as they are traversing the Golgi, and depending on the cell type, it can get packaged into vesicles (alongside calcium) for secretion. So, they meet a lot of enzymes along the way, but harbour no catalytic activity themselves (as far as we know!).

kyleblarson 2y ago

Does the spelling of the word "ageing" look strange to anyone else? I looked it up and it appears to be acceptable, but why not "pageing", "cageing" etc?

deleted 2y ago
[deleted]
deleted 2y ago
[deleted]

napierzaza 2y ago

[dead]

elif 2y ago

IN MICE**

LoganDark 2y ago
All statements relating to biology should be assumed to be about mice unless stated otherwise.

bregav 2y ago

Some are noting that this is "in mice", but a recently approved new drug for schizophrenia suggests that a connection between mucins and brain function in humans is more than speculative: https://en.wikipedia.org/wiki/Xanomeline/trospium_chloride https://en.wikipedia.org/wiki/Xanomeline/trospium_chloride Brand name Cobenfy, this drug is a combination of a muscarinic agonist and a muscarinic antagonist. Notably its therapeutic component was initially developed as an alzheimer's treatment, and IIRC showed positive results in the few trials that were performed in the 90's before the drug was abandoned due to side effects (until now).

walterbell 2y ago

Stanford explainer, https://news.ycombinator.com/item?id=43233003 https://news.ycombinator.com/item?id=43233003 > What if a critical piece of the puzzle of brain aging has been hiding in plain sight? While neuroscience has long focused on proteins and DNA, a team of Stanford researchers dared to shift their gaze to sugars – specifically the complex sugar chains that cover all our cells like chain mail.. Shi’s project was the first to investigate how age affects its sugary armor – the glycocalyx.. “Modulating glycans has a major effect on the brain – both negatively in aging, when these sugars are lost, and positively, when they are restored,” Shi says. “This opens an entirely new avenue for treating brain aging and related diseases.”