[HN Gopher] Mucins keep the brain safe and could guard against a...
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Mucins keep the brain safe and could guard against ageing
Author : walterbell
Score : 158 points
Date : 2025-02-28 08:31 UTC (2 days ago)
(HTM) web link (www.nature.com)
(TXT) w3m dump (www.nature.com)
| Trasmatta wrote:
| ...in mice.
| owlninja wrote:
| We have to start somewhere.
| account-5 wrote:
| True but "in mice" in the title would save a lot of time.
| SapporoChris wrote:
| I would settle for a non-click bait title.
| the__alchemist wrote:
| Thought-terminating Cliche.
| alt227 wrote:
| Surprising how many times this exact comment is posted on HN
| these days.
|
| Arent all human treatments tested on mice first?
| elif wrote:
| 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 wrote:
| explainer: https://archive.is/vMfmZ
|
| open access paper: 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 wrote:
| 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 wrote:
| "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/clea
| ning-u...
| ein0p wrote:
| I should have asked GPT before wasting everyone's time.
| GPT4.5 says that while lethal and transmissible pathogens
| can be built with adenoviruses, nearly all research with
| them is done on replication-deficient viruses, and does not
| improve their transmissibility, pathogenicity, and does not
| expand the host range.
| hakaneskici wrote:
| Why is it called "gain of function" if there's no gain of
| function?
|
| > why lots of people are so against it
|
| Hearing "GoF is NOT GoF" just makes me suspicious
| _instinctively_ , that's all - no bad intention.
| toast0 wrote:
| This is a nomenclature issue. But as a non-involved
| person, the key function of a virus is
| distribution/virulance. Gain of Function means increasing
| the effectiveness of the key function. So making a virus
| spread more, making an immune cell more effective against
| pathogens, making a retina cell more sensitive to light.
|
| Gaining An Additional Function is not the same thing,
| although the confusion is understandable.
| card_zero wrote:
| They used AAV, which is a virus that doesn't cause disease.
|
| https://en.wikipedia.org/wiki/Adeno-associated_virus
|
| AAV9 can pass the blood-brain barrier (already), it says
| there.
| freehorse wrote:
| I assume, without reading the paper or being an expert, that
| they use the virus as a vector for their genetic payload,
| while also removing the reproduction instructions from it.
| Similar to the astrazeneca vaccines for covid19.
| card_zero wrote:
| The virus is like that, but naturally occuring:
|
| https://en.wikipedia.org/wiki/Helper_dependent_virus
|
| "The most widely known dependovirus is adeno-associated
| virus (AAV)"
|
| It's "replication-deficient", a "satellite virus": it
| requires help (from a different virus) to replicate.
|
| (I don't know this stuff either, I'm just summarizing
| Wikipedia at you.)
| hirenj wrote:
| Fun fact: The AAVR (AAV receptor) is itself a
| glycoprotein (carrying the precise type of glycosylation
| they are trying to repair with the "gene therapy").
| Haven't read up what replacement gene dose ended up
| being, but entirely within realms of possibility that
| this could influence which cells get corrected.
| card_zero wrote:
| So that's, what, a protein on the outside of the cell
| that lets the virus in, like its own particular catflap?
| And you're saying this portal is made of mucus, and mucus
| is what they want to repair, and therefore ... nope,
| can't piece the conclusion together, sorry. "Could
| infuence", as in?
| hirenj wrote:
| Catflap is a surprisingly apt analogy. In this case it is
| an endocytosis receptor, that selects cargo for uptake.
| Differs from virus to virus of course, but I could see
| changes in the sugars on these proteins altering
| behaviour. Mucus/mucins are basically proteins very
| heavily modified with sugars, so you have this common
| system that is adapted to do different things.
| card_zero wrote:
| ( _endocytosis,_ into-cell-doing.)
| hirenj wrote:
| 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 wrote:
| 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 wrote:
| 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 wrote:
| thanks for doing work on this and thanks for commenting on it
| on hn!!
| FollowingTheDao wrote:
| Copper and calcium seem to stimulate some mucins.
| polskibus wrote:
| What can we eat/do to boost this barrier?
| greggsy wrote:
| 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.
| deadbabe wrote:
| Eat chlorophyll and spirulina to boost brain slime!
| bloomingeek wrote:
| Isn't it time for a serious conversation about the wonderful
| health benefits of ivermectin? (:
| giardini wrote:
| 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 wrote:
| Should ivermectin be removed from this list?
|
| https://en.wikipedia.org/wiki/WHO_Model_List_of_Essential_M
| e...
| hirenj wrote:
| We don't know is the answer. However, if you were coral, then I
| would suggest increasing the amount of symbiotic algae, which
| stimulates mucin secretion (probably a nutrient boost).
|
| A brain normally doesn't receive enough sunlight for this
| strategy to work for humans.
| UnreachableCode wrote:
| Algae omegas possibly?
| moffkalast wrote:
| Mount LEDs inside the skull, got it.
| bamboozled wrote:
| More time in the sun ? :)
| card_zero wrote:
| Eating nori, sounds reasonable, I feel smarter already.
| alt227 wrote:
| Inside your head? Maybe we need a new 'head sunroof' or
| similar.
| aruggirello wrote:
| Or replace bone with glass, ending up like those famous
| crystal skulls from Mexico. But algae might then bloom and
| grow in uncontrolled fashion. You'd need plancton then, and
| maybe krill or even fish too - enter skull aquariums.
| gattr wrote:
| A few decades from now, in the biohacker/modder community:
| "Recap your noggin with our reinforced-glass-ceramic dome!".
| denniskubes wrote:
| Prebiotics like Akkermansia help improve the mucin layer in the
| colon. Lower amounts of these beneficial bacteria actually
| contribute to gut health. The weird part is Akkermansia
| actually eats the mucin layer. You would think that would cause
| a less dense mucous layer, but the presence of Akkermansia
| actually causes goblet cells in your gut produce more mucin
| which strengthens the mucous layer. We also know that gut
| health can and does affect the nervous system.
| nothinggoesaway wrote:
| It's a fair and good question.
|
| From "Endothelial Glycocalyx Preservation -- Impact of
| Nutrition and Lifestyle" (2023) [1]:
|
| Vitamin D; omega-3 supplementation; dietary sulfur (onion,
| garlic, leek, kale, broccoli, cauliflower, cabbage...);
| intermittent fasting
|
| (edited for formatting)
|
| [1] https://pmc.ncbi.nlm.nih.gov/articles/PMC10255458/
| FollowingTheDao wrote:
| 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-mu...
| amelius wrote:
| https://pubmed.ncbi.nlm.nih.gov/35975308/
|
| How could NAC help here, if it reduces mucus?
| hirenj wrote:
| 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 wrote:
| The enzyme MUC(1-whatever) makes mucin.
|
| https://www.uniprot.org/uniprotkb?query=mucin&facets=model_o.
| ..
| hirenj wrote:
| 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 wrote:
| 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?
| elif wrote:
| IN MICE**
| LoganDark wrote:
| All statements relating to biology should be assumed to be
| about mice unless stated otherwise.
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