Different autism risk genes
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.
SOURCE: https://www.sciencedaily.com/releases/2022/02/220202111727.htm
Hello,
FTP service is a community for DJ’s & fans that helps you gain full access to exclusive electronic music various artists, singles trax. http://0daymusic.org
https://0daymusic.org/premium.php
Best Regards, DJ Gianko
As a Newbie, I am continuously exploring online for articles that can help me. Thank you
I like this web site because so much utile stuff on here : D.
Good day! I just wish to give you a huge thumbs up for your excellent information you have got here on this post. I am coming back to your blog for more soon. Good day! I just wish to give you a huge thumbs up for your excellent information you have got here on this post. I am coming back to your blog for more soon. נערות ליווי בקיסריה
Thank you for another informative site. Where else could I get that type of information written in such a perfect way? I have a project that I’m just now working on, and I’ve been on the look out for such info.
Hi there! I just want to offer you a huge thumbs up for your great info youve got here on this post. I am coming back to your website for more soon.
Hiya very nice site!! Guy .. Excellent .. Superb .. I’ll bookmark your web site and take the feeds also…I am satisfied to find so many useful information here in the publish, we want develop extra strategies in this regard, thanks for sharing.
Hello! I know this is kinda off topic however , I’d figured I’d ask. Would you be interested in exchanging links or maybe guest writing a blog post or vice-versa? My blog addresses a lot of the same topics as yours and I feel we could greatly benefit from each other. If you might be interested feel free to shoot me an email. I look forward to hearing from you! Fantastic blog by the way!
I am glad to be a visitant of this staring site! , thankyou for this rare information! .
I dugg some of you post as I cerebrated they were very helpful very helpful
Unquestionably believe that which you said. Your favorite justification seemed to be on the internet the simplest thing to be aware of. I say to you, I certainly get irked while people consider worries that they plainly do not know about. You managed to hit the nail upon the top and also defined out the whole thing without having side effect , people can take a signal. Will likely be back to get more. Thanks
Simply wanna comment on few general things, The website pattern is perfect, the content is really excellent. «Some for renown, on scraps of learning dote, And think they grow immortal as they quote.» by Edward Young.
I discovered your blog site on google and examine a number of of your early posts. Continue to maintain up the very good operate. I just additional up your RSS feed to my MSN Information Reader. Searching for forward to studying extra from you afterward!…
Perfectly composed written content, Really enjoyed studying.
Wonderful website. Plenty of helpful information here. I am sending it to some pals ans also sharing in delicious. And obviously, thank you to your effort!
Very interesting subject, thank you for putting up.
You made some first rate points there. I regarded on the internet for the issue and found most people will go along with along with your website.
It’s a pity you don’t have a donate button! I’d certainly donate to this brilliant blog! I guess for now i’ll settle for bookmarking and adding your RSS feed to my Google account. I look forward to fresh updates and will share this website with my Facebook group. Talk soon!
naturally like your web-site however you have to take a look at the spelling on quite a few of your posts. Many of them are rife with spelling problems and I in finding it very troublesome to inform the reality then again I will definitely come again again.
You have observed very interesting points! ps decent site. «In music the passions enjoy themselves.» by Friedrich Wilhelm Nietzsche.
Please let me know if you’re looking for a writer for your weblog. You have some really great articles and I believe I would be a good asset. If you ever want to take some of the load off, I’d love to write some material for your blog in exchange for a link back to mine. Please blast me an email if interested. Kudos!
Greetings! Quick question that’s totally off topic. Do you know how to make your site mobile friendly? My web site looks weird when viewing from my iphone 4. I’m trying to find a template or plugin that might be able to fix this problem. If you have any recommendations, please share. Many thanks!
Muchos Gracias for your article.Really thank you! Cool.
I’m extremely pleased to discover this website. I wanted to thank you for ones time just for this fantastic read!
My website: русское порно любительское
Muchos Gracias for your article.Really thank you! Cool.
My website: домашний секс со студентками
Thank you ever so for you blog. Really looking forward to read more.
My website: домашние оргазмы
I got what you intend,bookmarked, very decent website.
My website: русское домашнее порно
I reckon something truly special in this website.
My website: cartoon porn
I reckon something truly special in this website.
My website: секс азиаток
A round of applause for your article. Much thanks again.
My website: китайское порно
Ponto IPTV a melhor programacao de canais IPTV do Brasil, filmes, series, futebol
My website: китайское порно