Embargoed Autism Study in Journal Nature: Virtual Press Briefing

What: Virtual press briefing with researchers about the embargoed study being published in the journal Nature about the genetic and neurodevelopmental involvement of the protein CPEB4 in Autism Spectrum Disorder

View the embargoed press release here.

Who: Dr. Xavier Salvatella, Research Professor at the Institute for Research in Biomedicine, The Barcelona Institute of Science and Technology

PIO Contact: Nahia Barberia, Communications – IRB Barcelona, [email protected], +34 652769748

When: Tuesday, December 3, 2024 at 1 PM ET 

Where: Newswise Live Zoom Room (address will be included in follow-up email)

Media Register to Attend

TRANSCRIPT

Newswise Host: Hello and welcome to this Newswise Live virtual press briefing. We’re joined here today with researchers publishing a paper in the Journal Nature about Autism research. I’d like to ask Dr. Salvatella and Dr. Garcia to please introduce yourselves and tell us a little bit about your findings.

Dr. Xavier Salvatella: Hello. My name is Xavier Salvatella. I am a research professor in a Research Institute based in Barcelona called Institute for Research in Biomedicine IRB, Barcelona, where I lead a research group work in the field of molecular biophysics, and I am the lead author of the paper that has just been introduced. I will now ask Carla to introduce herself, and then we will tell you a little bit what the discovery that we report in this paper is. Carla. Go ahead. 

Carla Garcia: Hi, I’m Carla Garcia. I’m currently a Research Associate in Xavier’s lab here at IRB, Barcelona, and I did my thesis here, also with him. So my expertise is basically same one, and I’m a co first author of this paper.

Newswise Host: Tell us a little bit about what the findings include.

Dr. Xavier Salvatella: Indeed, the starting point of the story is a finding that was published actually in the very same journal Nature 2018 by my collaborator, Raul Bendev and his team, which discovered a very striking correlation between the onset of Autism and defect in one specific protein called CPEB4 more specifically, they discovered that the absence of a tiny region of sequence in this protein was very tightly associated with autism. However, in that paper, they did not provide a mechanism, a molecular mechanism that would explain why the loss of that tiny region of sequence would give rise to the series of processes which underlie autism. And that’s what we provide in the paper that will be published tomorrow. Okay, so we provide the molecular mechanism explaining why loss of that tiny region of sequence gives rise to autism. And yeah, go ahead with your question.

Newswise Host: Tell us a little bit about what that genetic process looks like and how that’s unique and different from previous discoveries about this mechanism.

Dr. Xavier Salvatella: In reality, about 20% of the cases of autism can be associated with a mutation in a specific gene. The rest of cases, about 80% of them are what we call idiopathic. This means that we cannot associate the disease to a mutation that is part of our genome. And there has been a mystery around why the disease occurs in the absence of a mutation, and that’s what we reveal in this in this paper, what we have discovered is that this protein, CPEB4, when it lacks this region of sequence, which I would like to clarify, is composed of about 1% of the sequence of this protein. So it’s a tiny, tiny fragment that is missing from it. But one is when this fragment is missing, the protein CPEB4 is unable to carry out its function. Let me just tell you what the function of CPEB4 is and then everything will make more sense. CPEB4  is a protein that is expressed in neurons and has the role to release a series of RNAs which have to be transcribed for an effective neuro development. The protein that regulates whether these RNAs are translated or not, is CPEB4 the translation of these RNAs, and therefore, the synthesis of all the proteins which have to exist for the efficient neuro development occurs when neurons are stimulated in a synapse, and the role of CPEB4  is to store these RNAs until the stimulation of the neurons takes place. Very interestingly, the process which allows CPEB4  to regulate the translation of these RNAs relies on a new phenomenon in biology, which has been discovered roughly 10 to 15 years ago, which is called biomolecular condensation. In this process, not one but several hundred copies of the CPEB4 molecule get together to form what we call protein droplets because CPEB4 interacts with these RNAs, these RNAs get stored in these protein droplets, waiting for the signal that will cause the dissociation of these droplets, the release of these RNAs, translation of these proteins, and therefore the efficient neurodevelopment.

Newswise Host: Media on the call, you’re welcome to please chat your questions, and I’ll ask the researchers your questions. Dr. Salvatella, Tell us a little bit more about the translation of this from the mouse model to what may come next with this, and also how this is built on previous studies in this area.

Dr. Xavier Salvatella: Yes. So as I was saying earlier, the ability of these protein droplets, storing the RNAs, to release them, therefore allowing their translation and the efficient neurodevelopment requires these droplets to be highly dynamic. They have to have the properties of a drop of oil in water. They have to be liquid. However, when this tiny fragment of CPEB4 is absent, these protein droplets lose their liquid character. They become an aggregate. They become solid. And when the neurons are stimulated, there’s a failure of these droplets to dissociate, a failure of these RNAs to be released, and a failure of these proteins to be synthesized, and therefore a decrease in neuro development that gives rise to autism. Okay. Now, answering your question, what does this knowledge mean in terms of a potential future development of a therapeutic approach for this disorder. Well aware of the fact that this tiny fragment is so critical for the ability of these droplets to store the RNAs and release them when needed, we have actually developed an approach for the moment only in vitro. This means with purified proteins in the test tube, but we have been able to show that if we actually generate an artificial sequence containing the fragment that is missing from CPEB4 if we deliver it to these droplets, this process of digitification, this process of loss of dynamic character that underlies autism can be prevented. And this, therefore, this provides the proof of the concept that this transition that causes autism is preventable if one is able to deliver the therapeutics to the right compartments in neurons. And therefore that’s what we are starting now to work in the lab with a hope in the future to prevent this process that we now have learned underlies autism. Of course, it will take a lot of work, and it will take, it will be necessary, to translate this knowledge from the in vitro experiments that we have done until now to experiments in cells, experiments in neurons and further down the line of therapeutic development as usual.

Newswise Host: And what does this look like for the development of a potential drug to deliver such a solution?

Dr. Xavier Salvatella: What is important from this work is that the results I will present suggest that if one would be successful at delivering this drug, this could be efficient for preventing the disorder. However, drug development is extremely complicated intellectual activity and quite empirical one, so it will require massive amounts of work and money and team work to get this to be a therapeutic, but at least now we know what the drug should do, which is an important first step, of course, in the development of any therapeutic.

Newswise Host: How is this approach to understanding autism and neurodevelopmental disorders unique from previous work?

Dr. Xavier Salvatella: It’s a good question. Actually, something that I didn’t mention earlier, but I think is relevant to mention now, is that these tiny fragments that I mentioned earlier, I didn’t label them properly, they are called micro exons. Micro exons are tiny regions of sequence which are known to be particularly frequent in proteins which are expressed in neurons. So we actually do know that many proteins, when they are expressed in neurons, our bodies introduce these specific regions of sequence called micro exons. And it is actually known that in several of proteins of that type, losing these micro exons is associated with all other neuro developmental disorders. Okay, so what is unique about this piece of work is that for the first time, we provide a specific explanation of how these micro exons work, and in this case, we can explain how they work, why their loss is problematic, and how it can be used the knowledge as a tool for development of therapeutics in the future. 

Newswise Host: So is there a potential? Yeah, go ahead, sorry. Is there a potential for developing some sort of screening for this before it develops?

Dr. Xavier Salvatella: That’s a really good question. It looks a little bit challenging, of course, CPEB4 is a neuronal protein, and it’s actually quite challenging to obtain information about the levels of of the two RNAs or two splice forms in neurons without any without a very invasive intervention, but we have been discussing with experts and there could be potential for developing approaches that could measure the levels in indirectly and provide information as to whether the deregulation of the splicing event that we discover in this paper and the previous one occur in a specific individual. So there are ways of doing this. We have not started doing the work, but we are ready in discussions with scientists to figure out if we can do this or not. That would be important, of course, because only for those patients, excuse me, those individuals with autism for which these levels of fragment are absent, would it make sense to compensate for that with the treatment that we are putting forward in the end of the paper?

Newswise Host: And what plans are there for the future studies to develop this further? You have something in mind.

Dr. Xavier Salvatella: Absolutely, the immediate thing to do is to find out if what works in the test tube, that means outside of cells. Let me just tell you that we can reproduce in vitro. That’s Carla’s expertise, the formation of these protein droplets we can reproduce in the test tube, the loss of dynamic character of this wicked droplets in vitro characterize it very well, and Carla has been able to show that these artificial fragments can be directed to the droplets and preserve their dynamic character. That’s fantastic, but now we need to check whether we can do this in cells, and it’s more specifically in neurons, which is more challenging than conventional cells. This is the first step. If this works in cells, then the next step will be to find out if we can obtain the same thing in an animal model of the condition. But that’s of course, in the future, the immediate thing to do is to test whether what happens in the test tube also happens in cells, and we are starting to do the work right now

Newswise Host: Tell us a little bit about the prevalence of autism and this type of developing autism spectrum disorder. How many patients is this likely to impact if it’s successful?

Dr. Xavier Salvatella: What we know for sure is that about, as I mentioned earlier, about 20% of the autism patients or individuals with this condition can be the disease or the disorder can be linked to a mutation. The 80% of them, by contrast, there is not such mutation that we can leave the disease with, and therefore they are called idiopathic. Potentially, what we have revealed in this paper, potentially could apply to many of these patients. So it could be, potentially a mechanism that applies to a very large majority of the individuals with autism, however, to be able to know which is the exact number, we would have to do a screening a massive number of individuals that this is unrealistic now, so the question still is out there as to this mechanism, does it apply to all of the 80% or only a fraction of them, we’ll find out in due time. Potentially, the number is high, but we don’t have the exact answer to your question, I’m afraid.

Newswise Host: Are there other types of these proteins, these micro exons, that warrant further investigation, similar to CPEB4, but that might be another formulation related to autism spectrum disorder as well as other conditions?

Dr. Xavier Salvatella: Yes, in fact, similar micro exons have been observed to exist in the neuronal forms of different proteins. It is known that the loss of these micro exons has been related with autism in a different protein, by the way, or to neuro psychotic disorders. So it may well be that the mechanism that we are putting forward is general. The unique feature of this study is that we provide the mechanism, and for the first time, we know why the micro reaction is so important. Hopefully our study will allow others to answer similar questions for other proteins containing micro exons and. The loss of which is linked to his order,

Newswise Host: Dr Salvatella and Dr Garcia. Thank you very much for joining us and sharing about your work. I’ve included the information for the communications office at your university and your research institute in the chat. And welcome any media on the call to follow up. If you have further questions like I said, we will be providing a recording and a transcript once we have those materials prepared. Thank you very much, doctors and best of luck with your paper and next steps. 

Dr. Xavier Salvatella: Thank you so much. Have a good evening or afternoon. Goodbye.