July 17, 2025 • 14 mins
🎙️ Episode 78: Interactions between TTYH2 and APOE Facilitate Endosomal Lipid Transfer
🧬 In this episode of PaperCast Base by Base, we explore the discovery and characterization of the interaction between the membrane protein TTYH2 and apolipoprotein E (APOE), and how this partnership drives lipid transfer within endosomal compartments.
🔍 Study Highlights:
Pull-down assays and mass spectrometry identified APOE as a binding partner of human TTYH2 in endosomes, and subcellular fractionation confirmed their colocalization within endosomal fractions. Cryo-EM structures of TTYH2–APOE complexes revealed that APOE binds to an epitope on the extracellular domain of the TTYH2 dimer, positioning lipid cargo for membrane insertion. In vitro lipid-transfer assays demonstrated that TTYH2 accelerates the exchange of lipids between APOE-containing particles and lipid bilayers, with specificity absent in the TTYH3 paralogue. Force spectroscopy and competitive binding assays further mapped the interaction to the C-terminal domain of APOE, highlighting a mechanism distinct from classical receptor-mediated uptake.
🧠 Conclusion:
This work uncovers TTYH2 as a novel endosomal lipid-transfer catalyst that may play a critical role in neuronal lipid homeostasis and offers a new target for understanding lipid trafficking in health and disease.
📖 Reference:
Sukalskaia A, Karner A, Pugnetti A, Weber F, Plochberger B & Dutzler R. (2025). Interactions between TTYH2 and APOE facilitate endosomal lipid transfer. Nature. https://doi.org/10.1038/s41586-025-09200-x
📜 License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/
On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics.
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Transcript
Episode Transcript
Available transcripts are automatically generated. Complete accuracy is not guaranteed.
(00:14):
Welcome to Base by Base, the paper cast that brings genomics
to you wherever you are. Have you ever stopped to think
about the incredibly complex highway system running inside
every single one of your cells? I mean, specifically how vital
fats and cholesterol lipids get transported around?
These aren't just for energy storage, you know, they're the
actual building blocks for all our cell membranes, absolutely
(00:37):
essential and maybe nowhere morecritical than in the brain.
Think about it, the brain. How do neurons, those vital
signaling cells, get the specific lipids they need,
especially from their support cells, the astrocytes?
It's not just a simple delivery,it's this really precise
regulated transfer. It's fundamental for brain
health. Now we know a key player here is
a polyproprotein E APOE. You could sort of picture it as
(00:59):
the cells dedicated delivery truck for lipids.
But here's the puzzle, the real mystery.
We kind of understand how these APOE packages get picked up at
the cell surface, brought inside.
But what happens next once they're inside the cell?
How did those lipids actually get unloaded into the right
compartments ready to be used inthis like major missing piece?
So today we're doing a deep diveand some fascinating new
(01:20):
research that seems to finally shed light on this crucial step.
It uncovers a whole new mechanism, and it has some
pretty surprising implications for cell health, especially
brain health. And here's where it gets really
interesting. And this might just open up new
ways to think about major diseases.
Yeah. And today we're highlighting
some really groundbreaking work.It's from a collaborative team,
researchers from the University of Zurich in Switzerland and the
(01:42):
University of Applied Sciences Upper Austria in Linz.
Their work has really pushed forward our understanding of how
these crucial lipids get moved around inside cells.
They've pinpointed a protein that was, well, basically
unknown in this role before Essential.
OK, right, let's untack this then, before we jump into their
specific discovery, maybe give us a clearer picture of APOE
(02:03):
itself. What is this protein exactly,
and why is it so important for lipid transport, particularly in
the brain? Sure.
So APOE is this really versatileprotein, a real workhorse
actually. Its main job is transporting
hydrophobic lipids, you know, things like cholesterol,
phosphol, lipids throughout the body and why you find it pretty
much everywhere. Its role in the brain is
(02:24):
uniquely critical. It's the main ape lipoprotein
there basically shuttles lipids back and forth between
astrocytes to support cells and the neurons, the signaling cells
and this constant exchange. It's absolutely vital for a
healthy brain function. Think building connections,
repairs. Right.
And I think many listeners mightrecognize the name APOE because,
well, it's often linked to a pretty significant health
(02:45):
challenge, isn't it? Precisely.
Yeah, you're right. There are three common versions
or isoforms, APOE 2, APOE 3, andAPOE 4.
And as you said, APOE 4 is probably the most well known
because it's a major genetic risk factor for late onset
Alzheimer's disease. So despite Apoe being so
critical and having this strong disease link the exact steps
(03:06):
inside the cell, like what happens after the cell takes up
these APUE lipid packages, they've been largely a black
box. We knew they got in, but how
they efficiently unloaded their cargo inside, that was a
mystery. OK, so that's where these Tweety
homologs, or TTY HS enter the story.
That's a name you don't forget. What were these proteins
originally thought to do, And why did the researchers even
(03:26):
suspect they might be involved in lipid transport instead of
their previously assumed job? Yeah, Tweety homologs, TTY, HS.
They're a family of membrane proteins found in eukaryotes, so
in our cells, too. And initially they were actually
classified incorrectly, it turnsout, as neon channels.
People thought they helped ions move across membranes.
(03:47):
But then more recent structural studies started showing
something different, a really distinct feature, this wide sort
of hydrophobic groove or cavity.It extends from the membrane
surface inward. And this unique structure LED
some people to hypothesize, well, maybe these TTY HS are
actually involved in lipid transfer perhaps between the
membrane and soluble carriers like APOE.
(04:08):
But, and this is key, there was no direct proof, no specific
interaction partners identified for this role.
Until now. That is the study really
provided that missing link. Right, this research sounds like
a fantastic example of using lots of different advanced
techniques together, like scientific detective work.
So how did the team first find this interaction between TTYH 21
specific Tweety and APOE? What was the initial hit?
(04:32):
Breakthrough came from a pretty smart approach to find out what
TTYH 2 actually binds to directly.
They use something called synthetic nano bodies, tiny very
specific antibody fragments for what are called pull down
experiments. It's kind of like fishing,
actually. They use these nano bodies as
bait to hook onto TTYH 2IN humancells, and they pulled out TTYH
(04:52):
2 along with anything physicallystuck to it.
Then they used mass spectrometry, A technique that
identifies molecules by weighingthem, essentially to see what
teens came along for the ride. And bingo, APOE showed up as one
of the most abundant proteins. They pulled down with TTYH 2.
That was a huge indicator, strongly suggesting they
interact. The first real aha moment.
(05:13):
OK, finding they interact in a lab setup is one thing, but
proving they actually meet up inside a cell in the right
location to do something meaningful, that's the next
step, right? How did they confirm that?
Absolutely, that's critical. So to check their location
inside the cell, they used a couple of powerful methods.
First, sub cellular fractionation.
This basically involves carefully breaking cells apart
(05:34):
and separating the different internal compartments based on
density. Think of it like sorting the
cells internal rooms and they found the TTY, H2 and APOE
consistently ended up in the same fractions, specifically
fractions containing endosomes. Endosomes.
Those are like the cells internal sorting stations.
Exactly where incoming stuff gets processed and sent to the
right place. Then they use confocal
(05:56):
fluorescence microscopy for the visual proof.
They tagged APOE and TTYH 2 withdifferent fluorescent colors and
they could literally see them lighting up together overlapping
in distinct spots inside the cells.
They also showed these spots overlapped with another protein
called Rab 9, which is known to be in late endosomes, so it
confirmed they were meeting in the right place right after APOE
(06:17):
gets taken into the cell. Crucial evidence.
And then came the really detailed picture, the structural
insights. They knew who was interacting
and where, but how do they physically connect?
How do they manage to see that at the atomic level?
Right, that's where cryo electron microscopy, cryo EM
really shown. It's an amazing technique that
let's you see molecular structures in incredible detail.
(06:38):
So they looked at TYH 2 bound APOE.
They did this with APOE both on its own dilipidated meaning
without lipids, and also as partof a whole lipoprotein particle
carrying its lipid cargo. And the cryo EM structures were
fascinating. They showed the APOE doesn't
just randomly bump into TTYH 2. It binds to a very specific spot
in epitope on a part of TTYH 2 that sticks out into the
(07:00):
endosome. And here's the critical part.
The way it binds positions the lipids carried by APOE right
next to that hydrophobic cavity,that sort of tunnel inside TTYH
2. This cavity basically acts as a
gateway it seems to allow the lipids to slide or diffuse
directly from APOE into the endosomal membrane.
They even saw in a high resolution structure of TTYH 2
alone, what looked like a continuous lipid belt inside
(07:22):
this cavity. It visually suggests how lipid
can move smoothly from APOE through TTYH 2 into the
membrane, like seeing the molecular handoff mechanism.
Wow. OK so they have The Who, the
where, and the how it looks structurally, but the killer
question is always does TTYH 2 actually speed up the lipid
transfer? Is it actively helping or just
(07:43):
passively holding APOE? Exactly, the functional test
does it actually do the job. To test this they set up these
really clever in vitro lipid transfer assays, basically
recreating the process in a controlled lab setting.
Now APOE particles can be a bit sticky and by non specifically
to membranes, which can mess up the results.
So they had to carefully optimize the experiment.
(08:04):
They used artificial membrane bubbles called liposomes,
designed to reduce this background stickiness.
Then they used lipids tagged with fluorescent markers, little
glowing tags. They could then watch in real
time how quickly these tagged lipids move from the APOE
particles over to the liposomes that contain TTYH 2.
And they needed to measure the actual kinetics too, right?
The speed and strength of the TTYH 2 APOE binding itself.
(08:26):
Yes, and for that they used something even more precise,
Single molecule force spectroscopy or SMFS.
This is pretty amazing stuff. It lets you measure the tiny
force needed to pull apart just one TTYH 2 molecule from one
APOE molecule. By doing this thousands of times
they could get really accurate measurements of how quickly they
bind and unbind the kinetic constants, and this confirmed
(08:49):
the interaction was strong enough but also dynamic enough
to allow for rapid lipid transfer.
OK, so after all that incrediblydetailed work from pull downs to
microscopy, cryoem, these functional assays, what were the
biggest takeaways, the most impactful findings for us?
Well, number one, they definitively showed TTYH 2 is a
real bona fide interaction partner of APOE that's
(09:09):
established. And critically, they show they
meet up consistently in endosomal compartments inside
the cell that puts them in exactly the right place at the
right time to handle lipid unloading after endocytosis.
And the structural stuff from Cryo EM, what was the key
message there about how they actually work together?
The cryo EM results were, yeah, incredibly revealing.
They showed APOE docs onto a specific site on TTYH 2 facing
(09:31):
the inside of the endosome. But the really crucial insight
was how this docking positions the lipids.
It lines them up perfectly with that hydrophobic cavity and TTYH
2. Essentially it creates a direct
path, a gateway for lipids to move from the APOE particle into
the membrane. Facilitated diffusion basically.
They also pinned down the C terminal part of APOE as being
(09:53):
key for this interaction. So it's a specific structured
handoff, not just random bumping.
Right, so the players, the location, the mechanism.
But did TTYH 2 actually make a difference to the speed?
Did it accelerate things? Yes.
Dramatically, those in vitro acids we talked about, they
showed a 14 fold acceleration inlipid transfer when TTYH 2 was
present. 14 fold. Wow.
Yeah, it's a huge difference. Not just a small nudge, but a
(10:16):
really substantial boost. This was clear, direct proof
that TTYH 2 acts as a catalyst, actively facilitating the lipid
exchange. It makes the whole unloading
process much, much more efficient.
Was this specific just to TTYH 2or could its relatives, the
other Tweety proteins, do the same thing?
Highly specific it seems. They tested TTYH 3 which is
(10:36):
closely related and it was much much slower at transferring
lipids. So this really points to TTYH 2
having a specialized role here. They also double checked it
wasn't acting as a lipid scram laws, which is a different
thing, just mixing lipids between membrane layers.
TTYH 2 facilitates directional transfer from APOE to the
membrane. And finally their cell based
experiments backed it all up. When they fed cells fluorescent
(10:59):
lipids carried by APOE, they sawthose lipids accumulating right
where TTYH 2 was located on the cell.
It happens in living systems. OK, let's zoom out a bit then.
Taking all this complex molecular detail, what does a
fundamentally change about how we understand cell biology?
And why should our listeners care, especially regarding
health? Well, I think the big picture is
that this study really defines anew class of proteins, these
(11:21):
Tweety humalogs, specifically TTYH 2, as facilitators of lipid
transfer, connecting soluble carriers like APOE to membranes.
It basically uncovers a whole step in how cells handle
lipoproteins internally that we didn't really understand before.
It explains how cells efficiently get the lipids out
of those APOE packages once they're inside.
(11:42):
That unloading step was a gap inour knowledge.
And thinking specifically about the brain where Apoe is so
dominant, what are the implications there, especially
with that Alzheimer's link, right?
While this TDY H2 mechanism is likely widespread, it's probably
particularly vital in the brain.Like we said, Apoe is the main
lipid transporter between astrocytes and neurons, So this
(12:04):
work explains that crucial unloading step that has to
happen after the APOE particles bind to receptors and get pulled
inside brain cells. It allows for that lipid
exchange within the endosome. This adds a really important
piece to the puzzle of brain lipid metabolism, and given the
APOE 4 link to Alzheimer's understanding these molecular
details well, it could genuinelyopen doors for new therapeutic
(12:27):
ideas. Maybe targeting TYH 2 could help
modulate lipid delivery in the brain.
It's early days, but possible. It definitely sounds like it
opens up a lot of new questions.Did the authors mention any
limitations? And what are the obvious next
steps for researchers wanting tobuild on this?
Yeah, they did acknowledge some technical challenges.
APOE itself can be tricky to work with.
It changes shape. It likes to stick to things.
(12:49):
That makes experiments harder. Looking forward, a really
crucial question is does TTYH 2 interact differently with the
different APOE isoforms? APOE 2E3E4?
If say it doesn't work as well with APOE 4, that could be a
direct link to the disease mechanism that needs
investigating urgently. Also, what about the other
Tweety proteins, TTYH 1 and TYH 3?
(13:10):
What do they bind to? Do they have similar roles or
different ones? And there's still more to learn
about TTYH 2 itself. Like the part of the protein
that phases the cell cytoplasm, It's C terminal domain.
What's its role? It's also just fascinating, as
the author's note, how this mechanism and seems to echo
other lipid transport systems inthe cell, like ones involved in
cholesterol transport or autophagy.
It hints it may be a common conserve strategy cells used to
(13:32):
manage lipids. So if someone listening takes
away just one key message from this deep dive, what should that
be? I'd say the core message is that
this research identifies TTYH 2 as a vital, previously unknown
catalyst. It efficiently unloads essential
lipids from a Poe inside our cells, specifically within
endosomes. It's a fundamental biological
(13:53):
process, super important for keeping lipid balance,
especially in the brain, and it gives us a new molecular player
to consider in neurological health and disease.
So what does this mean for fruitsize?
Maybe the design of future therapies for neurodegenerative
diseases We're getting lipid metabolism right in the brain is
looking increasingly critical. Definitely something to ponder.
(14:14):
This episode was based on an Open Access article under the
CCBY 4 Point O license. You can find a direct link to
the paper and the license in ourepisode description.
If you enjoyed this analysis, the best way to support Base by
Base is to subscribe or follow in your favorite podcast app and
leave us a five star rating. It only takes a few seconds but
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show. Thanks for listening and join us
(14:35):
next time as we explore more science base by Base.
Welcome to Base by Base, the paper cast that brings genomics
to you wherever you are. Have you ever stopped to think
about the incredibly complex highway system running inside
every single one of your cells? I mean, specifically how vital
fats and cholesterol lipids get transported around?
These aren't just for energy storage, you know, they're the
actual building blocks for all our cell membranes, absolutely
(00:37):
essential and maybe nowhere morecritical than in the brain.
Think about it, the brain. How do neurons, those vital
signaling cells, get the specific lipids they need,
especially from their support cells, the astrocytes?
It's not just a simple delivery,it's this really precise
regulated transfer. It's fundamental for brain
health. Now we know a key player here is
a polyproprotein E APOE. You could sort of picture it as
(00:59):
the cells dedicated delivery truck for lipids.
But here's the puzzle, the real mystery.
We kind of understand how these APOE packages get picked up at
the cell surface, brought inside.
But what happens next once they're inside the cell?
How did those lipids actually get unloaded into the right
compartments ready to be used inthis like major missing piece?
So today we're doing a deep diveand some fascinating new
(01:20):
research that seems to finally shed light on this crucial step.
It uncovers a whole new mechanism, and it has some
pretty surprising implications for cell health, especially
brain health. And here's where it gets really
interesting. And this might just open up new
ways to think about major diseases.
Yeah. And today we're highlighting
some really groundbreaking work.It's from a collaborative team,
researchers from the University of Zurich in Switzerland and the
(01:42):
University of Applied Sciences Upper Austria in Linz.
Their work has really pushed forward our understanding of how
these crucial lipids get moved around inside cells.
They've pinpointed a protein that was, well, basically
unknown in this role before Essential.
OK, right, let's untack this then, before we jump into their
specific discovery, maybe give us a clearer picture of APOE
(02:03):
itself. What is this protein exactly,
and why is it so important for lipid transport, particularly in
the brain? Sure.
So APOE is this really versatileprotein, a real workhorse
actually. Its main job is transporting
hydrophobic lipids, you know, things like cholesterol,
phosphol, lipids throughout the body and why you find it pretty
much everywhere. Its role in the brain is
(02:24):
uniquely critical. It's the main ape lipoprotein
there basically shuttles lipids back and forth between
astrocytes to support cells and the neurons, the signaling cells
and this constant exchange. It's absolutely vital for a
healthy brain function. Think building connections,
repairs. Right.
And I think many listeners mightrecognize the name APOE because,
well, it's often linked to a pretty significant health
(02:45):
challenge, isn't it? Precisely.
Yeah, you're right. There are three common versions
or isoforms, APOE 2, APOE 3, andAPOE 4.
And as you said, APOE 4 is probably the most well known
because it's a major genetic risk factor for late onset
Alzheimer's disease. So despite Apoe being so
critical and having this strong disease link the exact steps
(03:06):
inside the cell, like what happens after the cell takes up
these APUE lipid packages, they've been largely a black
box. We knew they got in, but how
they efficiently unloaded their cargo inside, that was a
mystery. OK, so that's where these Tweety
homologs, or TTY HS enter the story.
That's a name you don't forget. What were these proteins
originally thought to do, And why did the researchers even
(03:26):
suspect they might be involved in lipid transport instead of
their previously assumed job? Yeah, Tweety homologs, TTY, HS.
They're a family of membrane proteins found in eukaryotes, so
in our cells, too. And initially they were actually
classified incorrectly, it turnsout, as neon channels.
People thought they helped ions move across membranes.
(03:47):
But then more recent structural studies started showing
something different, a really distinct feature, this wide sort
of hydrophobic groove or cavity.It extends from the membrane
surface inward. And this unique structure LED
some people to hypothesize, well, maybe these TTY HS are
actually involved in lipid transfer perhaps between the
membrane and soluble carriers like APOE.
(04:08):
But, and this is key, there was no direct proof, no specific
interaction partners identified for this role.
Until now. That is the study really
provided that missing link. Right, this research sounds like
a fantastic example of using lots of different advanced
techniques together, like scientific detective work.
So how did the team first find this interaction between TTYH 21
specific Tweety and APOE? What was the initial hit?
(04:32):
Breakthrough came from a pretty smart approach to find out what
TTYH 2 actually binds to directly.
They use something called synthetic nano bodies, tiny very
specific antibody fragments for what are called pull down
experiments. It's kind of like fishing,
actually. They use these nano bodies as
bait to hook onto TTYH 2IN humancells, and they pulled out TTYH
(04:52):
2 along with anything physicallystuck to it.
Then they used mass spectrometry, A technique that
identifies molecules by weighingthem, essentially to see what
teens came along for the ride. And bingo, APOE showed up as one
of the most abundant proteins. They pulled down with TTYH 2.
That was a huge indicator, strongly suggesting they
interact. The first real aha moment.
(05:13):
OK, finding they interact in a lab setup is one thing, but
proving they actually meet up inside a cell in the right
location to do something meaningful, that's the next
step, right? How did they confirm that?
Absolutely, that's critical. So to check their location
inside the cell, they used a couple of powerful methods.
First, sub cellular fractionation.
This basically involves carefully breaking cells apart
(05:34):
and separating the different internal compartments based on
density. Think of it like sorting the
cells internal rooms and they found the TTY, H2 and APOE
consistently ended up in the same fractions, specifically
fractions containing endosomes. Endosomes.
Those are like the cells internal sorting stations.
Exactly where incoming stuff gets processed and sent to the
right place. Then they use confocal
(05:56):
fluorescence microscopy for the visual proof.
They tagged APOE and TTYH 2 withdifferent fluorescent colors and
they could literally see them lighting up together overlapping
in distinct spots inside the cells.
They also showed these spots overlapped with another protein
called Rab 9, which is known to be in late endosomes, so it
confirmed they were meeting in the right place right after APOE
(06:17):
gets taken into the cell. Crucial evidence.
And then came the really detailed picture, the structural
insights. They knew who was interacting
and where, but how do they physically connect?
How do they manage to see that at the atomic level?
Right, that's where cryo electron microscopy, cryo EM
really shown. It's an amazing technique that
let's you see molecular structures in incredible detail.
(06:38):
So they looked at TYH 2 bound APOE.
They did this with APOE both on its own dilipidated meaning
without lipids, and also as partof a whole lipoprotein particle
carrying its lipid cargo. And the cryo EM structures were
fascinating. They showed the APOE doesn't
just randomly bump into TTYH 2. It binds to a very specific spot
in epitope on a part of TTYH 2 that sticks out into the
(07:00):
endosome. And here's the critical part.
The way it binds positions the lipids carried by APOE right
next to that hydrophobic cavity,that sort of tunnel inside TTYH
2. This cavity basically acts as a
gateway it seems to allow the lipids to slide or diffuse
directly from APOE into the endosomal membrane.
They even saw in a high resolution structure of TTYH 2
alone, what looked like a continuous lipid belt inside
(07:22):
this cavity. It visually suggests how lipid
can move smoothly from APOE through TTYH 2 into the
membrane, like seeing the molecular handoff mechanism.
Wow. OK so they have The Who, the
where, and the how it looks structurally, but the killer
question is always does TTYH 2 actually speed up the lipid
transfer? Is it actively helping or just
(07:43):
passively holding APOE? Exactly, the functional test
does it actually do the job. To test this they set up these
really clever in vitro lipid transfer assays, basically
recreating the process in a controlled lab setting.
Now APOE particles can be a bit sticky and by non specifically
to membranes, which can mess up the results.
So they had to carefully optimize the experiment.
(08:04):
They used artificial membrane bubbles called liposomes,
designed to reduce this background stickiness.
Then they used lipids tagged with fluorescent markers, little
glowing tags. They could then watch in real
time how quickly these tagged lipids move from the APOE
particles over to the liposomes that contain TTYH 2.
And they needed to measure the actual kinetics too, right?
The speed and strength of the TTYH 2 APOE binding itself.
(08:26):
Yes, and for that they used something even more precise,
Single molecule force spectroscopy or SMFS.
This is pretty amazing stuff. It lets you measure the tiny
force needed to pull apart just one TTYH 2 molecule from one
APOE molecule. By doing this thousands of times
they could get really accurate measurements of how quickly they
bind and unbind the kinetic constants, and this confirmed
(08:49):
the interaction was strong enough but also dynamic enough
to allow for rapid lipid transfer.
OK, so after all that incrediblydetailed work from pull downs to
microscopy, cryoem, these functional assays, what were the
biggest takeaways, the most impactful findings for us?
Well, number one, they definitively showed TTYH 2 is a
real bona fide interaction partner of APOE that's
(09:09):
established. And critically, they show they
meet up consistently in endosomal compartments inside
the cell that puts them in exactly the right place at the
right time to handle lipid unloading after endocytosis.
And the structural stuff from Cryo EM, what was the key
message there about how they actually work together?
The cryo EM results were, yeah, incredibly revealing.
They showed APOE docs onto a specific site on TTYH 2 facing
(09:31):
the inside of the endosome. But the really crucial insight
was how this docking positions the lipids.
It lines them up perfectly with that hydrophobic cavity and TTYH
2. Essentially it creates a direct
path, a gateway for lipids to move from the APOE particle into
the membrane. Facilitated diffusion basically.
They also pinned down the C terminal part of APOE as being
(09:53):
key for this interaction. So it's a specific structured
handoff, not just random bumping.
Right, so the players, the location, the mechanism.
But did TTYH 2 actually make a difference to the speed?
Did it accelerate things? Yes.
Dramatically, those in vitro acids we talked about, they
showed a 14 fold acceleration inlipid transfer when TTYH 2 was
present. 14 fold. Wow.
Yeah, it's a huge difference. Not just a small nudge, but a
(10:16):
really substantial boost. This was clear, direct proof
that TTYH 2 acts as a catalyst, actively facilitating the lipid
exchange. It makes the whole unloading
process much, much more efficient.
Was this specific just to TTYH 2or could its relatives, the
other Tweety proteins, do the same thing?
Highly specific it seems. They tested TTYH 3 which is
(10:36):
closely related and it was much much slower at transferring
lipids. So this really points to TTYH 2
having a specialized role here. They also double checked it
wasn't acting as a lipid scram laws, which is a different
thing, just mixing lipids between membrane layers.
TTYH 2 facilitates directional transfer from APOE to the
membrane. And finally their cell based
experiments backed it all up. When they fed cells fluorescent
(10:59):
lipids carried by APOE, they sawthose lipids accumulating right
where TTYH 2 was located on the cell.
It happens in living systems. OK, let's zoom out a bit then.
Taking all this complex molecular detail, what does a
fundamentally change about how we understand cell biology?
And why should our listeners care, especially regarding
health? Well, I think the big picture is
that this study really defines anew class of proteins, these
(11:21):
Tweety humalogs, specifically TTYH 2, as facilitators of lipid
transfer, connecting soluble carriers like APOE to membranes.
It basically uncovers a whole step in how cells handle
lipoproteins internally that we didn't really understand before.
It explains how cells efficiently get the lipids out
of those APOE packages once they're inside.
(11:42):
That unloading step was a gap inour knowledge.
And thinking specifically about the brain where Apoe is so
dominant, what are the implications there, especially
with that Alzheimer's link, right?
While this TDY H2 mechanism is likely widespread, it's probably
particularly vital in the brain.Like we said, Apoe is the main
lipid transporter between astrocytes and neurons, So this
(12:04):
work explains that crucial unloading step that has to
happen after the APOE particles bind to receptors and get pulled
inside brain cells. It allows for that lipid
exchange within the endosome. This adds a really important
piece to the puzzle of brain lipid metabolism, and given the
APOE 4 link to Alzheimer's understanding these molecular
details well, it could genuinelyopen doors for new therapeutic
(12:27):
ideas. Maybe targeting TYH 2 could help
modulate lipid delivery in the brain.
It's early days, but possible. It definitely sounds like it
opens up a lot of new questions.Did the authors mention any
limitations? And what are the obvious next
steps for researchers wanting tobuild on this?
Yeah, they did acknowledge some technical challenges.
APOE itself can be tricky to work with.
It changes shape. It likes to stick to things.
(12:49):
That makes experiments harder. Looking forward, a really
crucial question is does TTYH 2 interact differently with the
different APOE isoforms? APOE 2E3E4?
If say it doesn't work as well with APOE 4, that could be a
direct link to the disease mechanism that needs
investigating urgently. Also, what about the other
Tweety proteins, TTYH 1 and TYH 3?
(13:10):
What do they bind to? Do they have similar roles or
different ones? And there's still more to learn
about TTYH 2 itself. Like the part of the protein
that phases the cell cytoplasm, It's C terminal domain.
What's its role? It's also just fascinating, as
the author's note, how this mechanism and seems to echo
other lipid transport systems inthe cell, like ones involved in
cholesterol transport or autophagy.
It hints it may be a common conserve strategy cells used to
(13:32):
manage lipids. So if someone listening takes
away just one key message from this deep dive, what should that
be? I'd say the core message is that
this research identifies TTYH 2 as a vital, previously unknown
catalyst. It efficiently unloads essential
lipids from a Poe inside our cells, specifically within
endosomes. It's a fundamental biological
(13:53):
process, super important for keeping lipid balance,
especially in the brain, and it gives us a new molecular player
to consider in neurological health and disease.
So what does this mean for fruitsize?
Maybe the design of future therapies for neurodegenerative
diseases We're getting lipid metabolism right in the brain is
looking increasingly critical. Definitely something to ponder.
(14:14):
This episode was based on an Open Access article under the
CCBY 4 Point O license. You can find a direct link to
the paper and the license in ourepisode description.
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(14:35):
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