July 22, 2025 • 25 mins
🎙️ Episode 83: Single-cell Analysis of dup15q Syndrome Illuminates Autism Mechanisms
🧬 In this episode of PaperCast Base by Base, we explore how single-cell RNA sequencing of patient-derived cortical organoids and postmortem brain tissue uncovers developmental and postnatal molecular changes in duplication 15q syndrome, a major genetic cause of autism.
🔍 Study Highlights:
The authors performed single-cell and single-nucleus transcriptomic profiling on cortical organoids and postmortem cortical samples from dup15q patients and matched controls to map cell-type specific gene expression changes across development and adulthood. They discovered a transient increase in glycolysis in deep-layer neurons and loss of layer-specific molecular identity during organoid differentiation. In postmortem adolescent and adult brains, upper-layer neurons exhibited increased transcriptional burden related to synaptic signaling, mirroring patterns observed in idiopathic autism. Spatial transcriptomics validated these disruptions in situ, and co-expression network analysis revealed preserved disease-associated modules linking metabolic dysregulation to synaptic dysfunction and neuronal hyperexcitability.
🧠 Conclusion:
This work highlights dynamic molecular reprogramming in dup15q neural lineages and provides a framework for understanding convergent pathways in syndromic and idiopathic autism.
📖 Reference:
Perez Y, Velmeshev D, Wang L, White ML, Siebert C, Baltazar J, Zuo G, Moriano JA, Chen S, Steffen DM, Dutton NG, Wang S, Wick B, Haeussler M, Chamberlain S, Alvarez-Buylla A, Kriegstein A. Single-cell analysis of dup15q syndrome reveals developmental and postnatal molecular changes in autism. Nature Communications. 2025;16:6177. doi:10.1038/s41467-025-61184-4
📜 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/
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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. What if unlocking the intricate
secrets of just one single rare genetic condition could suddenly
shine a light on fundamental truths about a much broader
neurodevelopmental disorder, oneaffecting millions worldwide?
(00:35):
It's a really compelling idea. It is, isn't it?
Imagine like a tiny genetic duplication that gives us this
unique, almost perfect window into how complex conditions like
autism spectrum disorder actually unfold.
Not just linking at one snapshotin time, but seeing it
dynamically continuously across someone's whole development.
That's the dream, really. So today we're going to dive
(00:57):
into exactly that challenge. We'll be peering into the, well,
the incredibly complex world of brain development.
From the very earliest stages. Exactly from the earliest fetal
stages using lab models right through to the complexities we
see in the adult brain. The goal is to pinpoint the the
precise cellular and molecular shifts that contribute to a
condition like this. And it's not just about the
(01:19):
single gene causing it. No, exactly.
It's about understanding that whole cascade of changes, trying
to bridge the gap between those very first developmental maybe
missteps and the complex issues seen later in life.
Precisely. And that's always been the huge
challenge in human brain research, hasn't it?
How do you genuinely connect those dots across an entire
(01:40):
lifespan? Especially when the changes are
so subtle. So subtle and so specific to
certain cells, it's incredibly difficult.
This work though, it offers a really powerful new way to look
at it. And that's why today we really
want to recognize some truly groundbreaking work.
It's from a team that has significantly pushed forward our
understanding of brain development, specifically in the
(02:02):
context of neurodevelopmental disorders.
Yeah, their. Approach gives us a new lens,
really. It does this investigation.
It really highlights the incredible effort led by Gonotan
Perez, Dmitri Valmashev, and Arnold Kristine.
Their main work was based at theEli and Edith Abroad Center of
Regeneration Medicine and Stem Cell Research, and also the
Department of Neurology at UCSF,University of California, San
(02:24):
Francisco. A major hub for this kind of
research. Absolutely.
But, you know, it wasn't just them working in isolation.
They had vital collaborations with researchers from the
Genomics Institute at UC Santa Cruz and also the University of
Connecticut Health Center. So bringing different expertises
together. Exactly that kind of
interdisciplinary approach, pulling together different
(02:44):
skills and perspectives, it's just essential when you're
tackling biological puzzles thiscomplex.
OK, let's really try and unpack this then.
Autism spectrum disorder, ASD, We know it's incredibly complex.
Famously so. It's not like one single thing.
It's more of a heterogeneous group of neurodevelopmental
(03:04):
conditions, right? Affecting how the brain develops
and functions. Which leads to that wide range
of clinical science communication differences,
repetitive behaviors, and so on.And it has very diverse genetic
underpinnings. But despite all that, Variety
research keeps suggesting kind of a convergence.
Yeah, convergence on common disease pathways in the brain,
it's like many different geneticstarting points might eventually
(03:26):
disrupt similar cellular or molecular processes downstream.
Yeah. Right.
Like different roads leading to a similar place, biologically
speaking. But the big question is how do
these pathways develop or changeor maybe go wrong over time,
especially during those criticalwindows and brain development?
And that's precisely where this condition dupe 15 Q syndrome
comes in. It offers that unique window you
(03:46):
mentioned earlier. So tell us about dupe 15Q.
Well, dupe 15 Q syndrome is actually a leading genetic cause
of ASD. It accounts for a pretty
significant chunk, maybe up to 3% of all ASD cases.
Wow, that's quite high for a single genetic.
'Cause it is. And it's not just, you know,
associated with the ASD, it's considered a direct genetic
cause. The syndrome itself is triggered
(04:08):
by having an extra copy, a duplication of a specific bit of
chromosome 15, specifically the region called 15Q11Q13.
Now, this duplication can happenin a couple of main ways.
How so? You can have an extra sort of
abnormal chromosome called an isodecentric chromosome 15, or
you can have what's called an interstitial duplication Ant dot
(04:30):
D UP15Q where that segment is just duplicated within the
normal chromosome 15 structure and the.
Key link to autism. The crucial thing to understand
is that the vast majority reallymost individuals diagnosed with
215 Q syndrome also meet the clinical criteria for autism
spectrum disorder. OK.
So if dupe 15 Q is such a clear genetic 'cause, why is it such a
(04:53):
powerful model for understandingASD more broadly, especially
since, as we said, ASD itself isso diverse?
That's a really critical question because dupe 15Q has
this known identifiable genetic basis, the duplication.
It lets researchers isolate and investigate very specific
molecular changes. So you know the starting.
(05:15):
Point exactly. Unlike an idiopathic ASD where
the cause often isn't clear, here we know the initial genetic
event and this allows for a truly dynamic investigation.
Not just a single snapshot. Right.
You can see how these changes unfold across different
developmental stages, and that'swhat this team did.
They looked at changes during fetal development using these
advanced organoid models. Mini brains in a dish.
(05:36):
Sort of, yeah. And then they track those
changes into post Natal life by carefully examining post mortem
human brain samples. You get both ends of the
spectrum. Precisely this two pronged
approach, it's vital for gettingthe full scope of the pathology.
It lets us ask, you know, do those initial disruptions, those
early developmental issues, do they just stick around?
Do they evolve? Do they trigger new problems
(05:58):
later on as the brain matures? Building that complete timeline
of the disease. That's the And that really is
the $1,000,000 question, isn't it?
How on earth do you even start to tangle those molecular
changes across such huge developmental time scales,
especially in something as intricate as dupe 15Q?
It's a massive challenge. And this is where the
methodology they use becomes so incredibly interesting.
(06:20):
They really employed a cutting edge sort of multi pronged
strategy. They absolutely did.
First off, they used something called single nucleus RNA
sequencing or SNRNA SEC OK. Break that down for us.
Think of it like taking a super detailed genetic snapshot, but
not of a whole chunk of tissue. Instead you're you're looking
inside individual cells, or technically the nuclei within
(06:41):
those cells. Why the?
Because that's where the RNA tells you which genes are
currently active. So this lets you see gene
activity in each specific cell type, neurons, glia, different
subtypes of neurons. Instead of just an average from
the whole sample. Exactly, bulk analysis averages
everything out and you lose all that crucial cell specific
detail. So they applied this SNR and
ASEC to 49 carefully selected snap frozen postmortem brain
(07:05):
tissue samples. From relevant brain, yes.
From key cortical regions often implicated in ASD the prefrontal
cortex, temporal cortex and anterior cingulate cortex.
These came from 11 individuals with dupe 15Q and 17
neurotypical controls. And they match them carefully.
Incredibly carefully matched forage, sex, the quality of the
(07:27):
RNARNA integrity to make sure the comparisons were valid.
It was a huge effort. And the result.
Over 345,000 individual single nuclei profiles.
Just a massive data set giving unparalleled cellular resolution
on the adult or adolescent brainstate.
OK, that covers the later stages, but what about those
critical early developmental phases, the ones that are so
hard to study directly in humans?
(07:48):
Right. For that they turn to single
cell RNA sequencing, SC RNA SEC,but this time on cortical
organoids. The mini brain models again.
Exactly. These are like small 3D clusters
of cells grown in a dish that mimic aspects of the developing
human brain cortex. They're made from patient
specific induced pluriotent stemcells, or ICS.
(08:08):
O you take adult cells like skincells.
Yep, reprogram them back to an embryonic like state and then
coax them into forming these brainlike structures.
Crucially, these organoids carrythe patient's own dupe 15Q
genetics. So you're modeling their
specific condition from the beginning.
Precisely, they analyzed these organoids at different time
points, 5000 and 150 days in thedish to capture different stages
(08:31):
of early fetal development. Adding another layer of data.
Another huge layer over 106,000 more expression profiles, giving
this unprecedented view into howgenes are behaving in developing
neurons and glia in the dupe 15Qcontext.
Wow, that is a phenomenal amountof data combining the organoids
in the postmortem tissue. But how did they make sure that
(08:53):
what they saw in the sequencing data at the single cell level
was actually happening spatiallywithin the brains real
structure? That's an excellent question.
You need to validate it right. They used a technique called
spatial transcriptomics. Specifically, they use the
Merscope platform. What does that do?
Imagine being able to not just count RNA molecules, but to see
(09:13):
exactly where they are within a slice of brain tissue at really
high resolution. Like a map of gene activity.
Exactly. A high definition map.
It allowed them to visually confirm that the cell type
specific disruptions they found was sequencing were actually
happening in the right places within the tissue sections, even
down to subcellular locations. It really anchors the sequencing
(09:35):
data to the physical reality of the brain.
OK, that's confirmation. And then how did they pull all
these different complex data sets together to find the big
picture, the main themes? For that, they used a powerful
computational approach called Gene Co Expression Network
Analysis, specifically a versioncalled HDWGCNA.
What does that analysis tell you?
(09:55):
It helps identify groups or modules of genes that tend to be
switched on or off together, suggesting they work together in
biological pathways. Crucially, it helped them find
disease associated gene modules that were conserved, meaning
they showed up consistently in both the organoid models and the
post mortem brain samples. So finding patterns that hold
(10:16):
true across development. Exactly.
That consistency points towards fundamental, recurring
biological themes linked to the disorder.
This whole combination of techniques, SCRN a SEC, SCRN a
SEC. On organoid spatial validation,
network analysis, it's just incredibly powerful.
It really sounds like it gives you this comprehensive view,
doesn't it? Both in a controlled
(10:36):
developmental model and in the actual human brain across a
significant part of the lifespan.
It really does. It sets the stage to answer that
key question. Do the early problems persist or
change over time? So let's get to it with all
these advanced tools. What did this deep dive actually
reveal about the journey of Duke15 Q in the brain?
What were the main findings? Well, the findings paint a
(10:59):
really clear picture of a dynamic molecular pathology.
It starts early and definitely evolves.
OK, start us early then in the organoids.
Right in the organoid models representing those early fetal
stages, they found something quite striking, a significant
increase in glycolysis. Glycolysis.
That's how cells breakdown sugarfor energy.
Exactly basic cellular energy production.
(11:22):
This metabolic shift was especially noticeable in the
early radial glia. Those are the brain stem cells,
the foundational builders, and also in the deep layer neurons
as they were forming. So right from the start the
energy usage is different. It seems so.
It suggests that these developing brain cells from
their earliest stages might be relying on a different, perhaps
less efficient, way of generating energy, or maybe
(11:44):
processing fuel differently thantypical cells.
This could represent a really fundamental metabolic
vulnerability, impacting the very energy supply needed for
building the brain correctly. Like the construction crew using
the wrong kind of fuel as you said before.
What effect did that have on theneurons themselves?
Well, that metabolic change appeared to have direct
consequences. They saw what they called
(12:05):
degraded layer specific marker expression in those deep layer
neurons. OK, so normally neurons mature
into specific types. They're supposed to migrate to
particular layers in the cortex,and each layer, each cell type,
has a distinct molecular identity, like a job description
defined by specific Barker genes.
(12:26):
These deep layer neurons, which are crucial for sending signals
out from the cortex, seem to be having an identity crisis.
They showed fewer of the typicalmarkers for mature deep layer
neurons. And instead.
Instead, they actually started expressing more markers usually
found in immature neurons, or even markers characteristic of
upper layer neurons which have totally different connections
(12:49):
and functions. So they weren't maturing
correctly or finding their proper place and role.
That's what it strongly suggests.
They weren't settling into theirproper functional identity.
And did this show up physically?Did the neurons look different?
Yes, it did. They also found aberrant
morphology. The structure was off.
How so? Instead of developing the
complex, highly branched structures that dendrites and
(13:10):
axons that neurons need for intricate brain wiring, these
deep layer neurons looked immature.
They had less complex branching in their neurites, those
projections that connect neurons.
So potentially less capacity forconnection.
Potentially, and they even validated this finding.
They took some of these 215 Q neurons from the organoids and
transplanted them into mice brains.
(13:31):
They saw the same thing. The neurons still show that
aberrant, less complex growth pattern in vivo.
That really strengthens the finding that this is a genuine
cellular dysfunction tied to theDuke 15 Q genetics, not just an
artifact of the dish. It suggests the brains wiring
might be compromised very early on.
OK, so these are significant foundational issues in early
(13:52):
development, Metabolism, cell identity, physical structure.
But what happens later as the brain matures into adolescence
and adulthood? Does the impact shift?
It absolutely seems to. When they looked at the
adolescent and adult post mortembrain samples using that's NRNA
SEC, they found a fascinating shift in which cells seem most
(14:12):
affected. Not the deep layer neurons
anymore. The focus shifted.
Now it was the upper layer projection neurons, specifically
those in layers 2 and three off You just call L23 neurons that
showed a heightened transcriptional burden.
Transcriptional burden, meaning more genes were dysregulated.
Yes, more signs of disrupted gene activity, and this
(14:33):
disruption was particularly concentrated in pathways related
to synaptic signaling. The communication between
neurons. Exactly the fundamental process
of how neurons talk to each other.
So this points to a clear progression.
You have these early metabolic and identity issues potentially
setting the stage and then laterin life different neuronal
subtypes. Specifically, these upper layer
neurons involved in more complexcortical processing connections
(14:55):
become significantly affected, particularly in how they
communicate. That's a really critical
progression to map out. Now here's a key question.
Did they find overlap between these depubnique findings and
what we know about idiopathic ASD?
You know, the cases without a clear single genetic cause.
Finding common ground there would be huge.
(15:15):
It would, and they did. That was definitely one of the
most exciting parts of the study.
They found significant shared molecular mechanisms and a clear
convergence with idiopathic ASD.OK, tell me more.
What's really eye opening is that many of the dysregulated
genes they found at Duke 15 Q were actually outside the
duplicated region on chromosome 15.
Really. So it's not just having extra
(15:36):
copies of those specific genes? No, they're precise.
Single nucleus sequencing identified over 5000
differentially express genes specific to certain cell types,
and these were genes that traditional bulk RNA sequencing,
which averages across all cells,would have completely missed.
It shows there are much broader downstream effects happening
(15:56):
across the genome. It's not just a simple gene
dosage problem from having that extra 15 Q segment.
It's like the initial genetic error triggers this ripple
effect. Exactly.
A cascade of effects across manyother genes and pathways.
And you're saying this ripple effect, these downstream
changes, actually mirror what's seen in other forms of autism?
That's what the data strongly suggests.
(16:17):
They found significant overlap in the specific genes being
dysregulated between dupe 15Q and idiopathic ASD, especially
in those vulnerable upper layer neurons we just talked.
About how much overlap? They highlighted 24 specific
genes that were differentially expressed in both conditions,
and remarkably, 23 out of those 24 showed the exact same trend.
(16:39):
You're consistently up regulatedor consistently down regulated
in both 215Q and idiopathic ASD samples.
And what kind of genes are these?
They're involved in absolutely critical neuronal functions,
things like synaptic function itself, neuroplasticity, which
is the brain's ability to adapt and change, and the structure,
the morphology of dendritic spines.
Dendritic spines. So those little bumps on neurons
(16:59):
were synapses. Formed exactly crucial for
receiving signals. We're talking about important
genes like SLITR, K5, CABP 1, and CNT and AP2, all known
players, and how neurons connectand communicate.
So real convergence at the levelof synaptic biology.
Yes. And looking broader at pathways,
they also noted dysregulation ofthe MAP Kirk signaling pathway.
(17:21):
Kirk Yeah, genes like MAP, K1 and NFIA were involved.
There's a really fundamental communication pathway inside
cells. It's well known for playing
crucial roles in neuronal differentiation, how neurons
grow their axons, and synaptic plasticity.
Finding this pathway disrupted in both conditions adds more
weight to the idea of common underlying mechanisms.
And what about that early metabolic issue?
(17:42):
Did that tie into the later findings?
It seems to be a core part of the story.
The metabolic reprogramming finding was incredibly robust
that gene Co expression analysis, The HDWGCNA really
highlighted a highly preserved glycolysis associated module, a
network of genes related to glycolysis specifically in those
organoid deep layer neurons. So the energy problem is a
(18:04):
consistent theme. It strongly reinforces the idea
that this metabolic dysregulation, this altered
energy processing is a fundamental mechanism in Duke 15
Q and it likely contributes downstream to those problems
they saw with neuron projection with synaptic function, maybe
even contributing to neuronal hyper excitability where neurons
(18:25):
become overly active, OK. One more thing on the findings,
were these changes seen uniformly across the different
brain regions they looked at, orwas there regional variation?
Another key insight there was significant regional
specificity. Where was it most pronounced?
The prefrontal cortex. The Pfc generally showed the
most alterations in gene expression compared to the other
regions they studied. And the Pfc is critical.
(18:47):
For executive functions, planning, decision making,
social cognition, complex behaviors, functions often
affected in ASD, and intriguingly, the changes in the
Pfc were often related to the organization of the cortical
cytoskeleton. The internal scaffolding of the
neurons. Exactly which is essential for
their structure, their shape andmaintaining connections.
(19:08):
So if you pull all this together, you really see this
dynamic evolving molecular storyin dupe 15Q.
Yeah, it really paints a picture.
It starts with that early metabolic hit, potentially
involving glycolysis affecting foundational cells, and then
later specific neuronal subtypes, particularly those
upper. Later neurons in regions like
the Pfc become especially vulnerable, showing problems
(19:30):
with synaptic communication, mirroring patterns also seen in
idiopathic ASD. This is.
Such a detailed picture, this deep dive offers incredible
insights really into how these early developmental issues can
ripple through and manifest quite differently in later
stages of a neurodevelopmental disorder.
So what does this whole timelineof molecular changes actually
(19:51):
mean for our broader understanding and maybe more
importantly, for potential interventions for DO 15?
Q Yes, but maybe for autism morebroadly.
Well, first, this study providesthis remarkably clear
demonstration. That the molecular impact of
dupe 15 Q isn't static, it's truly a dynamic process shifting
across development. From metabolism to synapses.
(20:12):
Right, we see those early metabolic and morphological
issues in the deep layer neuronsin the organoids transitioning
later to that significant synaptic dysfunction,
particularly in the upper layer neurons in the post Natal brain.
Understanding this dynamic progression is absolutely
critical. And it also says something about
the tools used, right? The Organoids.
It really does. This work powerfully validates
(20:34):
these cortical organoids as highly effective tools not just
for modeling early developmentalaspects of human brain
disorders, but maybe importantly, for predicting some
of the later changes. They found this really strong
link between specific transcription factors, the genes
that control other genes that were active in the organoids,
and the downstream genes those factors regulate in the actual
(20:57):
postmortem brain samples. That connection is a kind of
breakthrough for validating these lab models as genuinely
predictive of what might be happening in vivo.
That's huge for future research using these models, and the
implications for finding that common ground with idiopathic
ASD seem massive too. If you see similar cellular
problems in both, does that opennew therapeutic avenues?
(21:18):
Absolutely. That's perhaps one of the most
significant implications. Identifying these shared
molecular changes, especially around synaptic regulation in
those upper layer neurons strongly suggests common
underlying pathways, which meanswhich means potential shared
therapeutic targets. If we can really understand and
effectively target the core mechanisms causing trouble in
(21:39):
DUB 15 QA condition with a knowngenetic cause, it might
genuinely open doors for therapies relevant to much
broader range of autism cases. So if different genetic starting
points converge on similar cellular problems.
Then treatments aimed at those common cellular problems could
potentially help many more individuals.
It shifts the focus from just the initial cause to the
(22:01):
downstream functional consequences.
And that early metabolic finding, does that suggest a
specific angle? It really does.
The robustness of that increasedglycolysis finding early on
suggests metabolic reprogrammingcould be a really fundamental
mechanism. It's not just about, you know,
having enough energy. It implies that altering how
cells produce energy could fundamentally contribute to
(22:23):
those later problems. The alter neuron shape, the
synaptic dysfunction, maybe eventhe hyper excitability.
So could intervening at the metabolic level early on be a
strategy? It's certainly a possibility
worth exploring. Understanding and potentially
normalizing those early metabolic vulnerabilities might
be a way to intervene before thefull cascade of synaptic and
(22:45):
structural problems fully manifests.
It opens up a different therapeutic window.
It really does. OK, So acknowledging the power
of this study, what are some of the limitations or the next
steps needed? Well, the researchers themselves
acknowledge that organoids, while incredibly powerful, are
still models. They don't replicate the full
complexity of a mature living brain.
They don't capture every aspect of post Natal development or all
(23:08):
the intricate cells cell interactions within the brain's
environment. Still work to be done there.
Definitely further research is needed to understand precisely
how that early metabolic burden leads to the specific changes in
neuron shape, identity, and function that are observed in
vivo. Making that full mechanistic
link is the next big step. But this study provides a
foundation. An incredible foundation, this
(23:30):
data set is an incredibly rich resource for future studies.
Researchers can now dive much deeper into specific gene
networks identified here, figuring out their precise
contribution to DUB 15Q pathophysiology.
It really does set the stage fordeveloping more targeted
therapies, focusing on these very specific cellular
vulnerabilities at different points of development.
(23:52):
So bringing it all together, what does this mean for you, our
listener? This really detailed
investigation reveals that DUB 15 Q syndrome isn't just one
static thing. It's characterized by this truly
dynamic progression of molecularchange specific to certain cell
types unfolding across development.
It seems to start with these early metabolic shifts, almost
(24:12):
like an altered power source forbuilding the brain, and then
progresses to involve specific problems with synapses and cell
structure, especially in key neuron populations needed for
higher order brain function and.Crucially, these findings really
highlight shared molecular pathways, shared problems
between Duke 15Q and idiopathic autism.
(24:34):
This suggests that understandingthe precise cellular weak spots
in one condition could genuinelyshed light on potential
therapies for the other. Allowing us to maybe focus
interventions on specific cellular issues at just the
right time during critical developmental windows.
Exactly. It opens up possibilities for
much more precise interventions.Which leads to a final thought
perhaps, what does this kind of understanding mean for how we
(24:56):
might approach interventions forneurodevelopmental disorders in
the future? Not just treating symptoms, but
maybe targeting the very developmental trajectory of the
brain itself. 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 our
episode description. If you enjoyed this analysis,
(25:17):
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It only takes a few seconds but makes a huge difference in
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Thanks for listening and join usnext 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. What if unlocking the intricate
secrets of just one single rare genetic condition could suddenly
shine a light on fundamental truths about a much broader
neurodevelopmental disorder, oneaffecting millions worldwide?
(00:35):
It's a really compelling idea. It is, isn't it?
Imagine like a tiny genetic duplication that gives us this
unique, almost perfect window into how complex conditions like
autism spectrum disorder actually unfold.
Not just linking at one snapshotin time, but seeing it
dynamically continuously across someone's whole development.
That's the dream, really. So today we're going to dive
(00:57):
into exactly that challenge. We'll be peering into the, well,
the incredibly complex world of brain development.
From the very earliest stages. Exactly from the earliest fetal
stages using lab models right through to the complexities we
see in the adult brain. The goal is to pinpoint the the
precise cellular and molecular shifts that contribute to a
condition like this. And it's not just about the
(01:19):
single gene causing it. No, exactly.
It's about understanding that whole cascade of changes, trying
to bridge the gap between those very first developmental maybe
missteps and the complex issues seen later in life.
Precisely. And that's always been the huge
challenge in human brain research, hasn't it?
How do you genuinely connect those dots across an entire
(01:40):
lifespan? Especially when the changes are
so subtle. So subtle and so specific to
certain cells, it's incredibly difficult.
This work though, it offers a really powerful new way to look
at it. And that's why today we really
want to recognize some truly groundbreaking work.
It's from a team that has significantly pushed forward our
understanding of brain development, specifically in the
(02:02):
context of neurodevelopmental disorders.
Yeah, their. Approach gives us a new lens,
really. It does this investigation.
It really highlights the incredible effort led by Gonotan
Perez, Dmitri Valmashev, and Arnold Kristine.
Their main work was based at theEli and Edith Abroad Center of
Regeneration Medicine and Stem Cell Research, and also the
Department of Neurology at UCSF,University of California, San
(02:24):
Francisco. A major hub for this kind of
research. Absolutely.
But, you know, it wasn't just them working in isolation.
They had vital collaborations with researchers from the
Genomics Institute at UC Santa Cruz and also the University of
Connecticut Health Center. So bringing different expertises
together. Exactly that kind of
interdisciplinary approach, pulling together different
(02:44):
skills and perspectives, it's just essential when you're
tackling biological puzzles thiscomplex.
OK, let's really try and unpack this then.
Autism spectrum disorder, ASD, We know it's incredibly complex.
Famously so. It's not like one single thing.
It's more of a heterogeneous group of neurodevelopmental
(03:04):
conditions, right? Affecting how the brain develops
and functions. Which leads to that wide range
of clinical science communication differences,
repetitive behaviors, and so on.And it has very diverse genetic
underpinnings. But despite all that, Variety
research keeps suggesting kind of a convergence.
Yeah, convergence on common disease pathways in the brain,
it's like many different geneticstarting points might eventually
(03:26):
disrupt similar cellular or molecular processes downstream.
Yeah. Right.
Like different roads leading to a similar place, biologically
speaking. But the big question is how do
these pathways develop or changeor maybe go wrong over time,
especially during those criticalwindows and brain development?
And that's precisely where this condition dupe 15 Q syndrome
comes in. It offers that unique window you
(03:46):
mentioned earlier. So tell us about dupe 15Q.
Well, dupe 15 Q syndrome is actually a leading genetic cause
of ASD. It accounts for a pretty
significant chunk, maybe up to 3% of all ASD cases.
Wow, that's quite high for a single genetic.
'Cause it is. And it's not just, you know,
associated with the ASD, it's considered a direct genetic
cause. The syndrome itself is triggered
(04:08):
by having an extra copy, a duplication of a specific bit of
chromosome 15, specifically the region called 15Q11Q13.
Now, this duplication can happenin a couple of main ways.
How so? You can have an extra sort of
abnormal chromosome called an isodecentric chromosome 15, or
you can have what's called an interstitial duplication Ant dot
(04:30):
D UP15Q where that segment is just duplicated within the
normal chromosome 15 structure and the.
Key link to autism. The crucial thing to understand
is that the vast majority reallymost individuals diagnosed with
215 Q syndrome also meet the clinical criteria for autism
spectrum disorder. OK.
So if dupe 15 Q is such a clear genetic 'cause, why is it such a
(04:53):
powerful model for understandingASD more broadly, especially
since, as we said, ASD itself isso diverse?
That's a really critical question because dupe 15Q has
this known identifiable genetic basis, the duplication.
It lets researchers isolate and investigate very specific
molecular changes. So you know the starting.
(05:15):
Point exactly. Unlike an idiopathic ASD where
the cause often isn't clear, here we know the initial genetic
event and this allows for a truly dynamic investigation.
Not just a single snapshot. Right.
You can see how these changes unfold across different
developmental stages, and that'swhat this team did.
They looked at changes during fetal development using these
advanced organoid models. Mini brains in a dish.
(05:36):
Sort of, yeah. And then they track those
changes into post Natal life by carefully examining post mortem
human brain samples. You get both ends of the
spectrum. Precisely this two pronged
approach, it's vital for gettingthe full scope of the pathology.
It lets us ask, you know, do those initial disruptions, those
early developmental issues, do they just stick around?
Do they evolve? Do they trigger new problems
(05:58):
later on as the brain matures? Building that complete timeline
of the disease. That's the And that really is
the $1,000,000 question, isn't it?
How on earth do you even start to tangle those molecular
changes across such huge developmental time scales,
especially in something as intricate as dupe 15Q?
It's a massive challenge. And this is where the
methodology they use becomes so incredibly interesting.
(06:20):
They really employed a cutting edge sort of multi pronged
strategy. They absolutely did.
First off, they used something called single nucleus RNA
sequencing or SNRNA SEC OK. Break that down for us.
Think of it like taking a super detailed genetic snapshot, but
not of a whole chunk of tissue. Instead you're you're looking
inside individual cells, or technically the nuclei within
(06:41):
those cells. Why the?
Because that's where the RNA tells you which genes are
currently active. So this lets you see gene
activity in each specific cell type, neurons, glia, different
subtypes of neurons. Instead of just an average from
the whole sample. Exactly, bulk analysis averages
everything out and you lose all that crucial cell specific
detail. So they applied this SNR and
ASEC to 49 carefully selected snap frozen postmortem brain
(07:05):
tissue samples. From relevant brain, yes.
From key cortical regions often implicated in ASD the prefrontal
cortex, temporal cortex and anterior cingulate cortex.
These came from 11 individuals with dupe 15Q and 17
neurotypical controls. And they match them carefully.
Incredibly carefully matched forage, sex, the quality of the
(07:27):
RNARNA integrity to make sure the comparisons were valid.
It was a huge effort. And the result.
Over 345,000 individual single nuclei profiles.
Just a massive data set giving unparalleled cellular resolution
on the adult or adolescent brainstate.
OK, that covers the later stages, but what about those
critical early developmental phases, the ones that are so
hard to study directly in humans?
(07:48):
Right. For that they turn to single
cell RNA sequencing, SC RNA SEC,but this time on cortical
organoids. The mini brain models again.
Exactly. These are like small 3D clusters
of cells grown in a dish that mimic aspects of the developing
human brain cortex. They're made from patient
specific induced pluriotent stemcells, or ICS.
(08:08):
O you take adult cells like skincells.
Yep, reprogram them back to an embryonic like state and then
coax them into forming these brainlike structures.
Crucially, these organoids carrythe patient's own dupe 15Q
genetics. So you're modeling their
specific condition from the beginning.
Precisely, they analyzed these organoids at different time
points, 5000 and 150 days in thedish to capture different stages
(08:31):
of early fetal development. Adding another layer of data.
Another huge layer over 106,000 more expression profiles, giving
this unprecedented view into howgenes are behaving in developing
neurons and glia in the dupe 15Qcontext.
Wow, that is a phenomenal amountof data combining the organoids
in the postmortem tissue. But how did they make sure that
(08:53):
what they saw in the sequencing data at the single cell level
was actually happening spatiallywithin the brains real
structure? That's an excellent question.
You need to validate it right. They used a technique called
spatial transcriptomics. Specifically, they use the
Merscope platform. What does that do?
Imagine being able to not just count RNA molecules, but to see
(09:13):
exactly where they are within a slice of brain tissue at really
high resolution. Like a map of gene activity.
Exactly. A high definition map.
It allowed them to visually confirm that the cell type
specific disruptions they found was sequencing were actually
happening in the right places within the tissue sections, even
down to subcellular locations. It really anchors the sequencing
(09:35):
data to the physical reality of the brain.
OK, that's confirmation. And then how did they pull all
these different complex data sets together to find the big
picture, the main themes? For that, they used a powerful
computational approach called Gene Co Expression Network
Analysis, specifically a versioncalled HDWGCNA.
What does that analysis tell you?
(09:55):
It helps identify groups or modules of genes that tend to be
switched on or off together, suggesting they work together in
biological pathways. Crucially, it helped them find
disease associated gene modules that were conserved, meaning
they showed up consistently in both the organoid models and the
post mortem brain samples. So finding patterns that hold
(10:16):
true across development. Exactly.
That consistency points towards fundamental, recurring
biological themes linked to the disorder.
This whole combination of techniques, SCRN a SEC, SCRN a
SEC. On organoid spatial validation,
network analysis, it's just incredibly powerful.
It really sounds like it gives you this comprehensive view,
doesn't it? Both in a controlled
(10:36):
developmental model and in the actual human brain across a
significant part of the lifespan.
It really does. It sets the stage to answer that
key question. Do the early problems persist or
change over time? So let's get to it with all
these advanced tools. What did this deep dive actually
reveal about the journey of Duke15 Q in the brain?
What were the main findings? Well, the findings paint a
(10:59):
really clear picture of a dynamic molecular pathology.
It starts early and definitely evolves.
OK, start us early then in the organoids.
Right in the organoid models representing those early fetal
stages, they found something quite striking, a significant
increase in glycolysis. Glycolysis.
That's how cells breakdown sugarfor energy.
Exactly basic cellular energy production.
(11:22):
This metabolic shift was especially noticeable in the
early radial glia. Those are the brain stem cells,
the foundational builders, and also in the deep layer neurons
as they were forming. So right from the start the
energy usage is different. It seems so.
It suggests that these developing brain cells from
their earliest stages might be relying on a different, perhaps
less efficient, way of generating energy, or maybe
(11:44):
processing fuel differently thantypical cells.
This could represent a really fundamental metabolic
vulnerability, impacting the very energy supply needed for
building the brain correctly. Like the construction crew using
the wrong kind of fuel as you said before.
What effect did that have on theneurons themselves?
Well, that metabolic change appeared to have direct
consequences. They saw what they called
(12:05):
degraded layer specific marker expression in those deep layer
neurons. OK, so normally neurons mature
into specific types. They're supposed to migrate to
particular layers in the cortex,and each layer, each cell type,
has a distinct molecular identity, like a job description
defined by specific Barker genes.
(12:26):
These deep layer neurons, which are crucial for sending signals
out from the cortex, seem to be having an identity crisis.
They showed fewer of the typicalmarkers for mature deep layer
neurons. And instead.
Instead, they actually started expressing more markers usually
found in immature neurons, or even markers characteristic of
upper layer neurons which have totally different connections
(12:49):
and functions. So they weren't maturing
correctly or finding their proper place and role.
That's what it strongly suggests.
They weren't settling into theirproper functional identity.
And did this show up physically?Did the neurons look different?
Yes, it did. They also found aberrant
morphology. The structure was off.
How so? Instead of developing the
complex, highly branched structures that dendrites and
(13:10):
axons that neurons need for intricate brain wiring, these
deep layer neurons looked immature.
They had less complex branching in their neurites, those
projections that connect neurons.
So potentially less capacity forconnection.
Potentially, and they even validated this finding.
They took some of these 215 Q neurons from the organoids and
transplanted them into mice brains.
(13:31):
They saw the same thing. The neurons still show that
aberrant, less complex growth pattern in vivo.
That really strengthens the finding that this is a genuine
cellular dysfunction tied to theDuke 15 Q genetics, not just an
artifact of the dish. It suggests the brains wiring
might be compromised very early on.
OK, so these are significant foundational issues in early
(13:52):
development, Metabolism, cell identity, physical structure.
But what happens later as the brain matures into adolescence
and adulthood? Does the impact shift?
It absolutely seems to. When they looked at the
adolescent and adult post mortembrain samples using that's NRNA
SEC, they found a fascinating shift in which cells seem most
(14:12):
affected. Not the deep layer neurons
anymore. The focus shifted.
Now it was the upper layer projection neurons, specifically
those in layers 2 and three off You just call L23 neurons that
showed a heightened transcriptional burden.
Transcriptional burden, meaning more genes were dysregulated.
Yes, more signs of disrupted gene activity, and this
(14:33):
disruption was particularly concentrated in pathways related
to synaptic signaling. The communication between
neurons. Exactly the fundamental process
of how neurons talk to each other.
So this points to a clear progression.
You have these early metabolic and identity issues potentially
setting the stage and then laterin life different neuronal
subtypes. Specifically, these upper layer
neurons involved in more complexcortical processing connections
(14:55):
become significantly affected, particularly in how they
communicate. That's a really critical
progression to map out. Now here's a key question.
Did they find overlap between these depubnique findings and
what we know about idiopathic ASD?
You know, the cases without a clear single genetic cause.
Finding common ground there would be huge.
(15:15):
It would, and they did. That was definitely one of the
most exciting parts of the study.
They found significant shared molecular mechanisms and a clear
convergence with idiopathic ASD.OK, tell me more.
What's really eye opening is that many of the dysregulated
genes they found at Duke 15 Q were actually outside the
duplicated region on chromosome 15.
Really. So it's not just having extra
(15:36):
copies of those specific genes? No, they're precise.
Single nucleus sequencing identified over 5000
differentially express genes specific to certain cell types,
and these were genes that traditional bulk RNA sequencing,
which averages across all cells,would have completely missed.
It shows there are much broader downstream effects happening
(15:56):
across the genome. It's not just a simple gene
dosage problem from having that extra 15 Q segment.
It's like the initial genetic error triggers this ripple
effect. Exactly.
A cascade of effects across manyother genes and pathways.
And you're saying this ripple effect, these downstream
changes, actually mirror what's seen in other forms of autism?
That's what the data strongly suggests.
(16:17):
They found significant overlap in the specific genes being
dysregulated between dupe 15Q and idiopathic ASD, especially
in those vulnerable upper layer neurons we just talked.
About how much overlap? They highlighted 24 specific
genes that were differentially expressed in both conditions,
and remarkably, 23 out of those 24 showed the exact same trend.
(16:39):
You're consistently up regulatedor consistently down regulated
in both 215Q and idiopathic ASD samples.
And what kind of genes are these?
They're involved in absolutely critical neuronal functions,
things like synaptic function itself, neuroplasticity, which
is the brain's ability to adapt and change, and the structure,
the morphology of dendritic spines.
Dendritic spines. So those little bumps on neurons
(16:59):
were synapses. Formed exactly crucial for
receiving signals. We're talking about important
genes like SLITR, K5, CABP 1, and CNT and AP2, all known
players, and how neurons connectand communicate.
So real convergence at the levelof synaptic biology.
Yes. And looking broader at pathways,
they also noted dysregulation ofthe MAP Kirk signaling pathway.
(17:21):
Kirk Yeah, genes like MAP, K1 and NFIA were involved.
There's a really fundamental communication pathway inside
cells. It's well known for playing
crucial roles in neuronal differentiation, how neurons
grow their axons, and synaptic plasticity.
Finding this pathway disrupted in both conditions adds more
weight to the idea of common underlying mechanisms.
And what about that early metabolic issue?
(17:42):
Did that tie into the later findings?
It seems to be a core part of the story.
The metabolic reprogramming finding was incredibly robust
that gene Co expression analysis, The HDWGCNA really
highlighted a highly preserved glycolysis associated module, a
network of genes related to glycolysis specifically in those
organoid deep layer neurons. So the energy problem is a
(18:04):
consistent theme. It strongly reinforces the idea
that this metabolic dysregulation, this altered
energy processing is a fundamental mechanism in Duke 15
Q and it likely contributes downstream to those problems
they saw with neuron projection with synaptic function, maybe
even contributing to neuronal hyper excitability where neurons
(18:25):
become overly active, OK. One more thing on the findings,
were these changes seen uniformly across the different
brain regions they looked at, orwas there regional variation?
Another key insight there was significant regional
specificity. Where was it most pronounced?
The prefrontal cortex. The Pfc generally showed the
most alterations in gene expression compared to the other
regions they studied. And the Pfc is critical.
(18:47):
For executive functions, planning, decision making,
social cognition, complex behaviors, functions often
affected in ASD, and intriguingly, the changes in the
Pfc were often related to the organization of the cortical
cytoskeleton. The internal scaffolding of the
neurons. Exactly which is essential for
their structure, their shape andmaintaining connections.
(19:08):
So if you pull all this together, you really see this
dynamic evolving molecular storyin dupe 15Q.
Yeah, it really paints a picture.
It starts with that early metabolic hit, potentially
involving glycolysis affecting foundational cells, and then
later specific neuronal subtypes, particularly those
upper. Later neurons in regions like
the Pfc become especially vulnerable, showing problems
(19:30):
with synaptic communication, mirroring patterns also seen in
idiopathic ASD. This is.
Such a detailed picture, this deep dive offers incredible
insights really into how these early developmental issues can
ripple through and manifest quite differently in later
stages of a neurodevelopmental disorder.
So what does this whole timelineof molecular changes actually
(19:51):
mean for our broader understanding and maybe more
importantly, for potential interventions for DO 15?
Q Yes, but maybe for autism morebroadly.
Well, first, this study providesthis remarkably clear
demonstration. That the molecular impact of
dupe 15 Q isn't static, it's truly a dynamic process shifting
across development. From metabolism to synapses.
(20:12):
Right, we see those early metabolic and morphological
issues in the deep layer neuronsin the organoids transitioning
later to that significant synaptic dysfunction,
particularly in the upper layer neurons in the post Natal brain.
Understanding this dynamic progression is absolutely
critical. And it also says something about
the tools used, right? The Organoids.
It really does. This work powerfully validates
(20:34):
these cortical organoids as highly effective tools not just
for modeling early developmentalaspects of human brain
disorders, but maybe importantly, for predicting some
of the later changes. They found this really strong
link between specific transcription factors, the genes
that control other genes that were active in the organoids,
and the downstream genes those factors regulate in the actual
(20:57):
postmortem brain samples. That connection is a kind of
breakthrough for validating these lab models as genuinely
predictive of what might be happening in vivo.
That's huge for future research using these models, and the
implications for finding that common ground with idiopathic
ASD seem massive too. If you see similar cellular
problems in both, does that opennew therapeutic avenues?
(21:18):
Absolutely. That's perhaps one of the most
significant implications. Identifying these shared
molecular changes, especially around synaptic regulation in
those upper layer neurons strongly suggests common
underlying pathways, which meanswhich means potential shared
therapeutic targets. If we can really understand and
effectively target the core mechanisms causing trouble in
(21:39):
DUB 15 QA condition with a knowngenetic cause, it might
genuinely open doors for therapies relevant to much
broader range of autism cases. So if different genetic starting
points converge on similar cellular problems.
Then treatments aimed at those common cellular problems could
potentially help many more individuals.
It shifts the focus from just the initial cause to the
(22:01):
downstream functional consequences.
And that early metabolic finding, does that suggest a
specific angle? It really does.
The robustness of that increasedglycolysis finding early on
suggests metabolic reprogrammingcould be a really fundamental
mechanism. It's not just about, you know,
having enough energy. It implies that altering how
cells produce energy could fundamentally contribute to
(22:23):
those later problems. The alter neuron shape, the
synaptic dysfunction, maybe eventhe hyper excitability.
So could intervening at the metabolic level early on be a
strategy? It's certainly a possibility
worth exploring. Understanding and potentially
normalizing those early metabolic vulnerabilities might
be a way to intervene before thefull cascade of synaptic and
(22:45):
structural problems fully manifests.
It opens up a different therapeutic window.
It really does. OK, So acknowledging the power
of this study, what are some of the limitations or the next
steps needed? Well, the researchers themselves
acknowledge that organoids, while incredibly powerful, are
still models. They don't replicate the full
complexity of a mature living brain.
They don't capture every aspect of post Natal development or all
(23:08):
the intricate cells cell interactions within the brain's
environment. Still work to be done there.
Definitely further research is needed to understand precisely
how that early metabolic burden leads to the specific changes in
neuron shape, identity, and function that are observed in
vivo. Making that full mechanistic
link is the next big step. But this study provides a
foundation. An incredible foundation, this
(23:30):
data set is an incredibly rich resource for future studies.
Researchers can now dive much deeper into specific gene
networks identified here, figuring out their precise
contribution to DUB 15Q pathophysiology.
It really does set the stage fordeveloping more targeted
therapies, focusing on these very specific cellular
vulnerabilities at different points of development.
(23:52):
So bringing it all together, what does this mean for you, our
listener? This really detailed
investigation reveals that DUB 15 Q syndrome isn't just one
static thing. It's characterized by this truly
dynamic progression of molecularchange specific to certain cell
types unfolding across development.
It seems to start with these early metabolic shifts, almost
(24:12):
like an altered power source forbuilding the brain, and then
progresses to involve specific problems with synapses and cell
structure, especially in key neuron populations needed for
higher order brain function and.Crucially, these findings really
highlight shared molecular pathways, shared problems
between Duke 15Q and idiopathic autism.
(24:34):
This suggests that understandingthe precise cellular weak spots
in one condition could genuinelyshed light on potential
therapies for the other. Allowing us to maybe focus
interventions on specific cellular issues at just the
right time during critical developmental windows.
Exactly. It opens up possibilities for
much more precise interventions.Which leads to a final thought
perhaps, what does this kind of understanding mean for how we
(24:56):
might approach interventions forneurodevelopmental disorders in
the future? Not just treating symptoms, but
maybe targeting the very developmental trajectory of the
brain itself. 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 our
episode description. If you enjoyed this analysis,
(25:17):
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