Deeparsi Prasad ’19 and Sivapriya Bhupalam


Cognition is, according to the Oxford dictionary, the “mental action or process of acquiring knowledge and understanding through thought, experience, and the senses.” In simpler terms, cognition is basically how we think. But what determines how we think? There has to be some influence from the environment. After all, the experiences we have can shape what we remember, and basically how we perceive the world. That can’t be the only thing though, because cognition comes from the brain, and our brains are made with the genetic information we get from our parents. How in the world can we even start to look at this question? Cognition is a very complicated process. There are many specific mechanisms involved, and multiple levels where things can go wrong. To learn about normal cognition, scientists will often look at cognitive disorders. By understanding more about where things go wrong, they can use that information to gain insight into cognition in general, and even try to develop treatments.

There are many different cognitive disorders, but we’ll focus on the genetic origins of Fragile X Syndrome, or FXS for short. This life long syndrome is the most common inherited cause of mental retardation and autism. It impairs the ability to think and learn, and causes behavioral, social, and emotional challenges. Some people with FXS also experience delayed speech, anxiety, hyperactive behavior, attention deficits, and even seizures1. So how exactly does FXS come about? Well, a process called RNA interference, or RNAi, plays a role.

First, let’s imagine that everyone is born with their own unique movie script. Like all movie scripts, there are dialogue lines that the actors will actually say and stage directions, which are instructions on how the cameras should be positioned, how the lines should be said, the lighting of the shot, etc. The stage directions are not said out loud, but are a part of the script and give directions on how to say the lines. Without them, we wouldn’t be able to make the right movie. For example, if a movie script has the lines:

       Hagrid: (intensely) Yer a wizard, Harry.

       Harry: (confused) I’m a what?

The instructions in italics about emotion and who says which line, are all part of the stage directions. The actors are also being recorded, so the movie can be played on TV, and this broadcast is the final product.

Of course, people aren’t literally born with movie scripts that direct their lives, but every person is born with a unique DNA sequence that acts like a movie script. DNA contains both “dialogue lines” and “stage directions”. The dialogue lines in DNA are called genes and they are made into something called mRNA. Just as what the actors say come from the script, this mRNA comes from DNA. The mRNA is how the dialogues are delivered by the actors, after taking stage directions into account. The mRNA is made into protein, which is the final product, like the broadcast of the film is the final product of the actors’ performances.

The “stage directions” in DNA are called non-coding RNAs. They’re instructions affecting how the proteins are made, without actually changing the DNA sequence or becoming proteins themselves, just like the stage directions in the script don’t make the final cut of the movie. Without instructions on how to say these lines, or how to express the genes, the final result of the body would be different, much like the final broadcast of the movie would be different. Since non-coding RNAs affect how the gene is made into protein without actually changing the DNA sequence, they are called epigenetic regulators, instead of genetic regulators (which actually do change the DNA sequence).

The process of making a movie, which starts with a movie script, is surprisingly similar to the process of making proteins, which starts with the DNA sequence.

There are different forms of non-coding RNAs, just like there are different types of stage directions. MicroRNAs, or miRNAs, are one kind of noncoding RNA. They work like the line in italics below:

       Ignore Harry’s line

       Hermione: I know who you are…you’re Harry Potter!

       Harry: Well, I don’t know who you are.

Hermione’s dialogue will be said out loud, but Harry’s dialogue won’t, because of the instructions telling him to ignore it, even though the dialogue itself isn’t crossed out in the script. Like the stage direction targeted a specific line to be ignored, each miRNA targets a precise mRNA, preventing it from getting made into protein, without actually changing the DNA sequence. This epigenetic process is called RNA interference, or RNAi. Studies show that this function of miRNAs could be involved in many neurological disorders2.

Now that we’ve explained RNAi, let’s talk about how FXS comes about. DNA, like a movie script, can have typos, or misprints, called mutations. There are many different kinds of mutations, just like there are many different kinds of typos, such as misspelling, deleting, or adding extra words in. One kind of mutation is when part of a DNA sequence is over-repeated. Imagine that the word read is supposed to appear in the stage direction lines. Instead of read appearing only a couple of times in the stage directions, there’s an entire page filled with the word, as if the writer wasn’t paying attention while typing the script and copied it over 200 times. When the actor reads the script, they’ll assume it’s a typo, white-out the page, and ignore it.

This is what Fragile X Syndrome actually looks like in the cell. In FXS, the organization of the DNA has a different appearance than normal, because of the mutation. So, the structure is more fragile, which is why it’s called “Fragile” X Syndrome7.

But sometimes there are dialogue lines that are in the middle or at the end of these repeats that are supposed to be said out loud. Since the actor whited-out the pages filled with the repeated word, they also ignore the dialogues at the end of the repetition. It won’t be a big deal to the movie if the lines aren’t important, but what if they are? It’ll affect the entire story, even if the rest of the script doesn’t have any typos. This is the kind of mutation that causes FXS. People with FXS are born with a certain non-coding sequence that is repeated over 200 times. Like the page filled with repeats in the movie script, this part of the DNA is “whited-out” through a process called DNA methylation, which causes the cell to also ignore a very important gene at the end of this repeat. This gene is called the fragile X mental retardation 1 gene or FMR1, which makes a protein called FMRP. FMRP plays an important role in brain development and learning3. Since the gene is “whited-out” in people with FXS, there is a lot less FRMP being made. This would be like the final cut of the movie not being broadcasted. The lack of FMRP is the main cause of FXS symptoms.

As recent studies have shown, another cause of symptoms could be the interaction between miRNA and FMRP, because it regulates many processes. The relationship between miRNA and FMRP could explain symptoms such as impairments in learning and memory. Let’s look at how miRNA interacts with FMRP and what this means for FXS.

A 2006 study found that specific miRNAs play an important role in determining when FMRP is made during development. Researchers found that many miRNAs come from the mutated repeat of FXS3. In the early stage of human development, the FMR1 gene and its surrounding repeated area are made into mRNA, which is made into FMRP. The miRNAs from the repeated section are also being made. This is what causes problems in those with FXS. Normally, the amount of miRNAs made from this section doesn’t affect how much FMRP gets made3, but in FXS, the over-repeated sequence makes many more miRNAs than normal. Like the over-repeated stage directions, the over-repeated miRNAs cause the cell to basically ignore the FMR1 mRNA. Because of this, there’s a major decrease in the amount of FMRP that is made. This would be like a lot of stage directions (that aren’t supposed to be there) telling the actor to ignore an important dialogue line, which would prevent the dialogue from showing up in the final movie cut.

This makes a huge difference because FMRP is responsible for managing other processes, so a lack of it can have a range of effects. For example, FMRP regulates brain development and neural connections3. If FMRP cannot regulate these processes, this can lead to the behavioral and cognitive deficits seen in FXS individuals. For example, an interaction between the FMR1 gene and miRNAs causes premature brain cell development. This affects learning and memory by affecting the size and strength of the connections between brain cells4, since the larger and stronger the connection, the stronger the memory. This is a potential reason why we see learning impairments in FXS individuals.

Not only does FMRP’s interaction with miRNA affect neuronal connections but it also controls how many miRNAs are made from the DNA5. miRNAs are created by using specific “machinery” proteins. Normally, FMRP increases the amount of machinery proteins, which in turn increases the amount of miRNA being made. But in FXS, this important interaction doesn’t happen because there isn’t much FMRP. The machinery protein levels decrease, and less miRNA is made. Since miRNAs have an important role in everything from brain cell development to immune responses, this could be a reason why there’s a variety of FSX symptoms.

Right now, there isn’t a concrete cure for FXS, but new research has developed a tool called DNA methylation editing that seems promising6. This tool has the potential to remove the methylation or “white-out” on the FMR1 gene in FXS. When scientists used this tool on cells from FXS patients, they were able to increase FMR1 mRNA and FMRP levels to almost the levels seen in normal, non-FXS cells. A benefit of this method is accuracy – it affects only the desired genes, without many side-effects on other genes. Also, when these cells were implanted into newborn mice, the mice could still express FMR1 mRNA and FMRP, meaning this method works in a living animal, and not just in individual cells. But, the treatment is most effective when done on cells before they fully become neurons. If done directly on neurons, the methylation, or the “white-out,” only slightly decreases6. Even with this drawback, DNA methylation editing can be used to study and potentially treat FXS.

Fragile X syndrome, like other cognitive disorders, involves complex mechanisms that are only recently being understood. There are so many processes that are occurring, so we don’t have a complete grasp on all of the specific mechanisms yet. Scientists are still learning how these processes affect learning and behavior in people, and even though a lot of progress is being made, there isn’t a cure yet. We do know that there is a genetic basis for these disorders and that environment, genetics, and epigenetics (amongst many other factors) all contribute to a person’s cognitive, physical, and physiological being. We might not fully understand what goes on behind the scenes to shape our thoughts and cognition yet, but the final result of this complicated movie script is something worth watching and learning about.

References

  1. Fragile X syndrome. (2018). Genetics Home Reference. Retrieved 17 April 2018, from https://ghr.nlm.nih.gov/condition/fragile-x-syndrome
  2. Sweatt, D.J., Meaney, M.J., Nestler, E.J., Akbarian, S. (2013). Epigenetic Regulation in the Nervous System: Basic Mechanisms and Clinical Impact. Academic Press.
  3. Santulli. (2015). microRNA: Medical Evidence: From Molecular Biology to Clinical Practice. Lin, Shi-Lung. Chapter 7: microRNAs and Fragile X Syndrome. Springer.
  4. Edbauer, D., Neilson, J.R., Foster, K.A., Wang, C., Seeburg, D.P., Batterton, M.N., Tada, T,. Dolan, B.M., Sharp, P.A., Sheng, M. (2010). Regulation of synaptic structure and function by FMRP-associated microRNAs miR-125b and miR-132. Neuron. 65(3): 373-384.
  5. Wan, R., Zhou, L., Yang, H., Zhou, Y., Ye, S., & Zhao, Q. et al. (2016). Involvement of FMRP in Primary MicroRNA Processing via Enhancing Drosha Translation. Molecular Neurobiology, 54(4): 2585-2594. http://dx.doi.org/10.1007/s12035-016-9855-9
  6. Liu, X., Wu, H., Krzisch, M., Wu, X., Graef, J., & Muffat, J. et al. (2018). Rescue of Fragile X Syndrome Neurons by DNA Methylation Editing of the FMR1 Gene. Cell, 172(5): 979-992.e6. http://dx.doi.org/10.1016/j.cell.2018.01.012
  7. Luo, L. (2016). Principles of neurobiology (p. 504). New York: Garland Science.

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