Different autism risk genes, same effects on brain development
Researchers use 3D, miniature models of the human brain to advance
disease understanding

Date:
February 2, 2022
Source:
Harvard University
Summary:
Researchers have found that three different autism risk genes
actually affect similar aspects of neuron development and the same
neuron types, although each gene acted through unique molecular
mechanisms.

Additionally, a person's specific genomic background fine-tuned the
genes' effects. The study was conducted using miniature 3D models,
or 'organoids,' of the human cerebral cortex, the part of the brain
responsible for cognition, perception, and language. The results
advance our understanding of autism spectrum disorder and are a
first step toward finding treatments for the condition.



FULL STORY ========================================================================== Autism spectrum disorder has been associated with hundreds of different
genes, but how these distinct genetic mutations converge on a similar
pathology in patients has remained a mystery. Now, researchers at Harvard University and the Broad Institute of MIT and Harvard have found that
three different autism risk genes actually affect similar aspects of
neural formation and the same types of neurons in the developing human
brain. By testing the genetic mutations in miniature 3D models of the
human brain called "brain organoids," the researchers identified similar overall defects for each risk gene, although each one acted through
unique underlying molecular mechanisms.


==========================================================================
The results, published in the journal Nature, give researchers a better understanding of autism spectrum disorder and are a first step toward
finding treatments for the condition.

"Much effort in the field is dedicated to understanding whether
commonalities exist among the many risk genes associated with
autism. Finding such shared features may highlight common targets for
broad therapeutic intervention, independent from the genetic origin of
disease. Our data show that multiple disease mutations indeed converge
on affecting the same cells and developmental processes, but through
distinct mechanisms. These results encourage the future investigation of therapeutic approaches aimed at the modulation of shared dysfunctional
brain properties," said senior author of the study Paola Arlotta, who
is the Golub Family Professor of Stem Cell and Regenerative Biology at
Harvard University and an institute member in the Stanley Center for Psychiatric Research at the Broad Institute.

The Arlotta lab focuses on organoid models of the human cerebral
cortex, the part of the brain responsible for cognition, perception,
and language. The models start off as stem cells, then grow into a 3D
tissue that contains many of the cell types of the cortex, including
neurons that are able to fire and connect into circuits. "In 2019, we
published a method to allow the production of organoids with the unique
ability to grow reproducibly. They consistently form the same types
of cells, in the same order, as the developing human cerebral cortex,"
said Silvia Velasco, a senior postdoctoral fellow in the Arlotta lab and
a co-lead author in the new study. "It is a dream come true to now see
that organoids can be used to discover something unexpected and very new
about a disease as complex as autism." In the new study, the researchers generated organoids with a mutation in one of three autism risk genes,
which are named SUV420H1, ARID1B, and CHD8. "We decided to start with
three genes that have a very broad hypothetical function.

They don't have a clear function that could easily explain what is
happening in autism spectrum disorder, so we were interested in seeing
if these genes were somehow doing similar things," said Bruna Paulsen,
a postdoctoral fellow in the Arlotta lab and co-lead author.

The researchers grew the organoids over the course of several months,
closely modeling the progressive stages of how the human cerebral cortex
forms. They then analyzed the organoids using several technologies:
single-cell RNA sequencing and single-cell ATAC-sequencing to measure
the changes and regulation in gene expression caused by each disease
mutation; proteomics to measure responses in proteins; and calcium
imaging to check whether molecular changes were reflected in abnormal
activity of the neurons and their networks.



========================================================================== "This study was only possible as a collaboration of several labs
that came together, each with their own expertise, to attack a complex
problem from multiple angles," said co-author Joshua Levin, an institute scientist in the Stanley Center and the Klarman Cell Observatory at the
Broad Institute.

The researchers found that the risk genes all affected neurons in a
similar way, either accelerating or slowing down neural development. In
other words, the neurons developed at the wrong time. Also, not all
cells were affected - - rather, the risk genes all impacted the same two populations of neurons, an inhibitory type called GABAergic neurons and
an excitatory type called deep- layer excitatory projection neurons. This pointed at selected cells that may be special targets in autism.

"The cortex is made in a very orchestrated way: each type of neuron
appears at a specific moment, and they start to connect very early. If
you have some cells forming too early or too late compared to when they
are supposed to, you might be changing the way circuits are ultimately
wired," said Martina Pigoni, a former postdoctoral fellow in the Arlotta
lab and co-lead author.

In addition to testing different risk genes, the researchers also produced organoids using stem cells from different donor individuals. "Our
goal was to see how changes in the organoids might be impacted by an individual's unique genetic background," said Amanda Kedaigle, an Arlotta
lab computational biologist and co-lead author.

When looking at organoids made from different donors, the overall changes
in neural development were similar, yet the level of severity varied
across individuals. The risk genes' effects were fine-tuned by the rest
of the donor genome.

"It is puzzling how the same autism risk gene mutations often show
variable clinical manifestations in patients. We found that different
human genomic contexts can modulate the manifestation of disease
phenotypes in organoids, suggesting that we may be able to use organoids
in the future to disentangle these distinct genetic contributions and
move closer to more a complete understanding of this complex pathology," Arlotta said.

"Genetic studies have been wildly successful at identifying alterations
in the genome associated with autism spectrum disorders and other neurodevelopmental conditions. The difficult next step on the path
to discovering new treatments is to understand exactly what these
mutations do to the developing brain," said Steven Hyman, who is a
Harvard University Distinguished Service Professor of Stem Cell and Regenerative Biology, the director of the Stanley Center at the Broad,
and a Broad Institute core member. "By mapping the alterations in
brain circuits when genetic variations are present, we can take the
tentative next step in the direction of better diagnoses and uncover
new avenues for therapeutic exploration." This research was supported
by the Stanley Center for Psychiatric Research, the Broad Institute
of MIT and Harvard, the National Institutes of Health (R01- MH112940, P50MH094271, U01MH115727, 1RF1MH123977), the Klarman Cell Observatory,
and the Howard Hughes Medical Institute. One of the cell lines (HUES66
CHD8) was created with support from the Simons Foundation and the National Institutes of Health.

special promotion Explore the latest scientific research on sleep and
dreams in this free online course from New Scientist -- Sign_up_now_>>> ========================================================================== Story Source: Materials provided by Harvard_University. Original written
by Jessica Lau.

Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Bruna Paulsen, Silvia Velasco, Amanda J. Kedaigle, Martina Pigoni,
Giorgia Quadrato, Anthony J. Deo, Xian Adiconis, Ana Uzquiano,
Rafaela Sartore, Sung Min Yang, Sean K. Simmons, Panagiotis
Symvoulidis, Kwanho Kim, Kalliopi Tsafou, Archana Podury, Catherine
Abbate, Ashley Tucewicz, Samantha N. Smith, Alexandre Albanese,
Lindy Barrett, Neville E. Sanjana, Xi Shi, Kwanghun Chung,
Kasper Lage, Edward S. Boyden, Aviv Regev, Joshua Z. Levin, Paola
Arlotta. Autism genes converge on asynchronous development of shared
neuron classes. Nature, 2022; DOI: 10.1038/s41586- 021-04358-6 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/02/220202111727.htm

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