New "Master-Controller" Molecule in Epilesy! - Mona Heiland, FutureNeuro, RCSI, Ireland
Find out about a new epilepsy discovery; how the microRNA-335 molecule plays a part in both Dravet Syndrome and Temporal Lobe Epilepsy and what this could mean for research going forward! All with post-doc researcher Mona Heiland!
Reported by Torie Robinson | Edited and produced by Carrot Cruncher Media.
Podcast
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00:00 Mona Heiland
“It seems to be able to translate it from, let's say, preclinical models to more human-related models, which was really nice to see.”00:09 Torie Robinson
Fellow homo sapiens! Welcome back to, or welcome to: Epilepsy Sparks Insights.
Now, I don’t know about you, but although epilepsy genetics and the new discoveries enthrall me, the details and terminology can get rather overwhelming at times! So, I really do appreciate it when we have a PPI scientist who can speak regular lingo!
So, our guest this week is the winner of the Education & Public Engagement Champion of 2024 award (at FutureNeuro), and today will share with us her microRNA discoveries ! May I introduce postdoc researcher Mona Heiland00:45 Mona Heiland
Hello, my name is Mona, I'm a post-doc in David Henshall's lab in the Royal College of Surgeons here in Dublin, Ireland, and my work is on microRNA-based therapies for epilepsy, especially drug-resistant epilepsies.01:02 Torie Robinson
And as a neuroscientist, what type of epilepsies are you focused on?01:07 Mona Heiland
Obviously drug-resistant epilepsies, which means these are epilepsy types which don't respond to the current anti-seizure medications, and that can be all kinds of epilepsies, from common temporal epilepsies (which are one of the most common forms of acquired epilepsy), but I'm also interested in genetic forms of epilepsies, mainly the ones which are caused by mutations in sodium channels.01:34 Torie Robinson
Just for people who aren't familiar, could you give us an overview of sodium channels? And… ‘cause, lots of us, I reckon - and certainly me included - if you say “sodium”, I just think of salt!01:44 Mona Heiland
Yeah! It has nothing to do about the salt which you put in our food - even if it's also sodium included in there! So, sodium ions are very important in the communication of neurons, so, our cells in the brain. So, how do neurons communicate? So, there's one neuron which gets information from the outside world - and obviously, it's so excited about it, it wants to give the information to all the other neurons in the brain! So, they have to communicate somehow and they do this by electrical signalling! So, we have the sodium ions; so, we have small... let's say, I call them “doors” or “gates” in our neurons. And they are not open all the time; they are like… you need to imagine these automatic doors, you know; [like] when you enter buildings and you approach them and then they're open, and then once you go through, they're closed again? They're a little bit like that. So, they're sensitive to changes of electricity in the neuron. So, if they sense a change in electricity, they will open up and then all the little sodium ions that can go inside the cell - and this causes then a change in the voltage! And they are all spread over the whole length of the axons (the axon is, let's say, the telephone line of a neuron to the next neuron) and they open and the signal can run along the axon to the next neuron! They are not open all the time (after a while they are closed again - otherwise there would constantly be electricity going on).
And there are other channels which are responsible to, basically, balance out the sodium signal. So, these are done by potassium. So, sodium and potassium; they are very important for our communication in the brain!
And let's say if there are mistakes in the proteins which form the sodium channels, let's say in a door; if the handle is missing or it doesn't close properly (these are basically mutations in the sodium channels), then we get problems with the signalling. So, if they're open too long, you get a lot of signalling. If they're not open enough, then you can get less signalling, and this is the case in epilepsy.
So, we have different types of sodium channels. Probably everyone heard about SCN1A - which causes Dravet Syndrome. So, Dravet Syndrome has a mutation in the SCN1A channel, and this channel is not functioning, so, it produces less signal. And then we have on the other hand something called SCN2A. So, SCN2A: if it's too long open, it can also cause seizures. And the interesting part is different sodium channels are located in different neuron types. Obviously, our brain has different neuron types, So, some are very chatty, they want to talk all the time, but imagine a room of people where everyone talks at the same time; it's just chaotic! So, we need also, someone who is coordinating that, and this we call “interneurons”. And there, for example, [in] Dravet Syndrome, the problem is [that] SCN1A is an interneuron, so they have, basically, disruption in the coordination. So, the interneurons that don't have enough signals, that's why all the other cells they are chatting too much and that's why it causes seizures.05:24 Torie Robinson
“Chatting too much” - gosh, that’s very polite way to put it isn't it?!05:27 Mona Heiland
Yeah! I try to fit in a very nice way to say well basically it's caught in epilepsy; it's chaos in the brain because all the neurons stay firing at the same time and the brain is just overwhelmed with it.05:41 Torie Robinson
Tell me about your research and particularly you've had a paper published about this work that you've done.05:47 Mona Heiland
So, I'm working on microRNAs...you did recently this beautiful podcast with David Henshall who already introduced us very well into the world of microRNAs, also, with his new book, which I really recommend to read because it gives the whole story of microRNAs!
So, in my work, I focus on a particular microRNA. So, microRNAs have numbers for…basically, that's how to get identified (not like genes with names, microRNAs have numbers), So, I'm working on microRNA-335. What I found is this microRNA is able to modulate the expression of voltage-gated sodium channels. So, basically how it works is,,, MicroRNA is (as you heard in your previous podcast) - they can basically regulate how much protein is produced by regulating gene expression. So, basically, they keep a balance in our body [to ensure] that we're not overflowing with some protein. However, if a microRNA level gets out of balance, like, say if you have too much or too less, the protein is also changed. So, what I found is if there not enough levels of microRNA-335 existing, sodium channel levels go up; so we have way more sodium channel expression in the neurons. So, basically, they fire more, they get more excited, basically you can get [an] epileptic phenotype.07:11 Torie Robinson
Ahhh!07:13 Mona Heiland
And then what we did [was] the opposite; is like, we increased the levels of microRNA-335 and we could see the opposite: basically, we could reduce down seizure severity and basically reduce down the sodium channels! So, basically, it goes into anti-epileptic properties. So, by modulating this one microRNA, we could basically modulate the brain excitability!07:41 Torie Robinson
And how did you find this out? Is this through working with rodents in the lab?07:47 Mona Heiland
So, how we found this microRNA is very interesting: it goes all the back to the origin where we did our first podcast about cannabidiol, CBD... So, I looked originally [at] which microRNA is changed after treatment of CBD - because I wanted to know if microRNAs are involved in the anti-seizure properties of CBD. And one of the microRNA is which was changed was microRNA-335.08:16 Torie Robinson
Ok.08:16 Mona Heiland
And then we found in blood plasma from a temporal lobe epilepsy patient: microRNA-335 is upregulated! And in the brain, it's downregulated! So, it's definitely (in epilepsy), the levels of microRNA-335 are disrupted. And we found this also in another epilepsy model. And it's very nice that this one microRNA comes up in different contexts, like, in human plasma, and brain tissue in a rodent model of epilepsy, and also, through a treatment with CBD. Because CBD works very well in Dravet Syndrome, we thought “Well, maybe because 335 can modulate sodium channels, maybe it could be a potential way how CBD works in Dravet Syndrome”. It's probably not the only solution (why it could work in Dravet Syndrome is a lot of things together), but we just thought we'd follow up what microRNA-335 is doing in general, and we found that it's really targeting sodium channels. Interesting is also, we tried it in iPSC cells (so, iPSC cells are stem cells from humans, so, it’s kind of a human model in the lab) and also, what we saw there [was] that even in these human cells; if we block microRNA-335, sodium channel levels were increased and they were more excitable! So, it seems to be also to be able to translate it from, let's say, preclinical models to more human-related models, which was really nice to see.10:01 Mona Heiland
So, what our plan is, basically… where we are [is] still in [a] very early phase, but it would be cool to, basically, take our microRNA and only go into neurons where SCN1A is and then we’d block this microRNA there, and, basically, could potentially increase sodium currents for SCN1A.10:25 Torie Robinson
Certainly keep your eye on Mona because this is flipping exciting. You know, you've got to figure out if it's… well, gonna “work” on certain organisms before you do it in humans, right? But, fingers crossed!10:38 Mona Heiland
We have the possibility to get resected brain tissue from epilepsy patients and do tests on those ones and this is the closest we get to humans at the moment. But the translation is still [in the] very early phase. So, we still need to find a way how to get it really later in a human being.11:01 Torie Robinson
If you have a resection at any point, I mean, it's not necessarily the most ideal thing, or it certainly can be, but rest assured that at least sometimes; your brain tissue removed could be used in research to help other people.11:13 Mona Heiland
Exactly. We are very appreciative that some people donate their tissue.11:18 Torie Robinson
Thank you so much to Mona - for explaining her work in a way that those who aren’t geneticists or neuroscientists can understand and enjoy!
Do check out more about Mona and her work on the website torierobinson.com (where you can also access the podcast, the video, and transcription of this episode), and if you haven’t already, don’t forget to like, comment, and subscribe to the channel, share this episode with your friends/colleagues/family members, whoever it might be (!) and, see you next week! -
Mona’s research is within the field of epilepsy, with a special focus on drug-resistant epilepsies and epilepsies caused by mutations in sodium channels. Her work centres on developing new therapy options through gene therapy and miRNA-based precision therapies, aiming to develop targeted therapeutic approaches that address the underlying genetic factors of those epilepsies and offering more personalised and effective treatment options for patients.
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MicroRNA-335-5p suppresses voltage-gated sodium channel expression and may be a target for seizure control: https://www.pnas.org/doi/10.1073/pnas.2216658120