RNA: A New Face in the Fight Against Neurodegeneration

Benjamin Kheyfets, Daniella Lorman, and Clem Doucette

Illustrations by: Phoebe Kinder

In the time it takes for you to read this sentence, over seven million cells in your body have died. And by this same time tomorrow, an unfathomable 10¹¹ more of your cells will have died and been replaced by new cells [1]. As alarming as this fact may sound, cell death, known as apoptosis, is an essential process to biological life. Apoptosis is critical in regulating a number of different bodily functions, ranging from the shapes of our organs to the amount of neurons in our nervous system [1]. However, certain conditions, like neurodegenerative diseases (NDDs), can cause apoptosis to go haywire, and when unplanned apoptosis occurs in the brain, it can result in catastrophic effects [2].

Right now, nearly 6.5 million Americans are suffering from some form of neurodegenerative disease, and estimates show that by 2030, as many as 12 million Americans may suffer from a NDD [3]. NDDs occur when the cells of the nervous system — including those of the brain, spinal cord, and nerves — function abnormally. Symptoms may be mild at first; short-term memory loss or coordination issues are common early indications of NDDs. However, as cells continue to deteriorate, symptoms such as loss of communication, seizures, and skin infections gradually increase in severity until they become fatal [4]. Unfortunately, no NDD is currently curable [5]. While some treatments do exist, such as medications and therapies, these interventions can only slow disease progression and manage symptoms. Given the ever-increasing urgency to find cures and treatments for NDDs, biotech and pharmaceutical companies have been heavily investing into research endeavors. A growing body of new research shows that genetic regulation, specifically via RNA, may play a huge role in the development of these diseases [6]. With this new and extensive research, RNA and its role in NDD development and progression has garnered a considerable spike in interest. This review will explore the role of RNA in neurodegenerative disease, with the goal of illuminating potential options for future treatments or cures.

RNA: More Than a Messenger     

In order to explore how RNA is involved in NDDs, it is essential to first understand RNA’s relationship to DNA. Imagine that you are in charge of developing a standardized cookbook for a nationwide fast food chain. Each restaurant receives the same cookbook, which has specific information about the ingredients needed to make each meal and exactly how to prepare it. Our DNA, found in the nuclei of most of our cells, is just like this cookbook. 

A DNA molecule consists of alternating sugars and phosphate groups; these components create DNA’s famous double helix structure. The “steps” of DNA’s ladder-like structure are made up of four different molecules called nucleotides: adenine, thymine, guanine, and cytosine, abbreviated with the letters A, T, G, and C [7]. A group of three letters (i.e. CCG, ATG, and ACT) is called a codon, which codes for an amino acid — the building blocks of proteins, and the ingredients in our recipes. Like recipes in a cookbook, these unique orderings of nucleotides provide the blueprints for creating different amino acids, and subsequently proteins. Just like cooking, where the ingredients you use determine the dish you end up with, the order of the amino acids in a protein determines the identity and function of that protein, and the order of the letters of DNA determine the genetic code of the individual. 

But how are these DNA recipes then turned into proteins? Enter: RNA. If DNA is a cookbook with recipes, then RNA is a copy of one recipe, containing the same information. However, RNA doesn’t write this recipe in the exact same code. Unlike DNA, RNA is a single stranded molecule with a slightly different chemical composition; in place of the DNA’s T, RNA uses a different nucleotide, uracil, abbreviated U [8]. Like in DNA, the order of nucleotides in RNA is critical. While the order of nucleotides in DNA determines an individual’s genetic code, the order of nucleotides of RNA determines the RNA’s function or the corresponding protein that will be made.

RNA’s most well-known role is that of the messenger RNA (mRNA) molecule. Messenger RNA serves as the genetic intermediary between DNA and ribosomes, or the organelles that manufacture proteins in our cells. Ribosomes are the chefs of our restaurant analogy. This process of creating mRNA from DNA is known as transcription, where, after being created, the mRNA recipe copy is brought to the ribosome (i.e. the chef). The ribosome then uses the mRNA recipe to create proteins; this process is known as translation. Because both transcription and translation are essential to cell functioning, they are regulated very closely to minimize the potential for missteps or errors.  

While bringing a copy of a recipe to the cook is the most common job of RNA, recent research has found that RNA does far more than just carry messages. Researchers have identified different classes of RNAs based on their length and function [9]. One such class is microRNA (miRNA); these mainly bind to mRNA molecules in order to block the ribosome from producing the mRNA’s encoded protein. If you are the ribosomal chef, this is like trying to read a smudged or water-stained copy of the recipe. While some portions of it may be legible, using it to prepare a meal would be virtually impossible. Another class of RNA is small interfering RNA (siRNA); these are short RNA molecules that bind to certain other RNA molecules, triggering their destruction. Cells can use siRNAs as a defense mechanism, protecting themselves from viruses and other foreign entities by destroying foreign nucleic acids [10]. In our restaurant analogy, siRNA would be a health inspector stopping by a restaurant where a number of customers have suffered severe food poisoning. To prevent further illnesses, the health inspector throws out the restaurant’s recipes causing sickness. Additionally, long noncoding RNAs (lncRNAs) are lengthy RNA molecules that, like siRNAs and miRNAs, do not actually code for proteins. Because of their length, they can take on many different shapes, and, depending on the specific characteristics of the RNA, can aid in the regulation of many different genes [9].

A Key Player in NDD Onset

Abnormalities in certain processes involving RNAs have been increasingly implicated in neurodegenerative diseases [11]. For example, a recent study suggested that flaws within proteins that bind to RNA, termed toxic aggregates, are a potential cause of certain NDDs [12]. Additionally, recent research has shown that NDDs can also be caused in part by the presence of too many RNA protein aggregates, which influence how mRNA is processed after it is formed. The role of RNA in NDDs is thought to be due to its self-assembling nature: certain RNAs can spontaneously assemble without the need for any energy or assistance from the cell [13].

One mechanism related to RNA that may contribute to the cell degradation characteristic of NDDs can be found in the functioning of lncRNAs [14]. LncRNAs are highly expressed in our central nervous system, and their expression is regulated so that they are only present in certain regions of the cell at certain times. This selective expression allows the cell to respond efficiently to environmental changes. In patients suffering from several NDDs, lncRNAs have been demonstrated to dysregulate proteins throughout the central nervous system, interfering with how certain proteins bind to other classes of proteins. For example, lncRNAs in Parkinson’s disease patients increase the rate at which ribosomes create certain proteins from RNA. Several types of lncRNAs have also been found to be dysregulated in patients with Huntington’s disease, becoming either over- or under-produced [15]. More specifically, researchers have found that certain lncRNAs play a role in the development and onset of Alzheimer’s. One known connection between RNA and Alzheimer’s disease includes the lncRNA BACE1-AS, which protects certain mRNAs from being degraded by certain miRNAs. This process can lead to the buildup of the plaques that contribute to Alzheimer’s. Another lncRNA named 51A leads to the formation of compounds that are involved in the onset of Alzheimer’s [16]. These molecules play an intricate role in NDDs and regulating neurons, and researching their dysregulation may be the key to improved treatments, and perhaps even cures [14]. 

RNA Drugs in NDD Treatments

In light of our new understanding of RNA’s role in NDDs, researchers have explored the efficacy of RNA-targeted drugs to address problems created by the dysregulation of proteins. In 2018, two new drugs, inotersen and patisiran, were approved in the United States and Europe to treat hereditary transthyretin (hATTR) amyloidosis [17]. This disease is caused by a mutated form of the gene that codes for transthyretin, a blood protein made in the liver. This mutation makes transthyretin dissolve less easily, so instead of freely traveling throughout the blood as it should, the protein clumps up around nerves and destroys neuronal tissue function. To treat this, inotersen and patisiran bind to the mRNA that encodes for the mutated form of transthyretin, blocking the ribosome from using this mRNA, preventing the clumps of mutant protein from forming. The drug inotersen, a modified form of DNA, accomplishes this by binding to the transthyretin mRNA and blocking it from producing mutated transthyretin proteins. Meanwhile, when patisiran (an siRNA drug) binds to the mutated transthyretin mRNA molecule, the cell destroys the mRNA strand [17]. Thinking back to our cookbook, the functioning of patisiran is like having your recipe copy come out either smudged and unclear, making it unreadable, or having the copy torn up, making it unusable. In either case, the meal doesn’t get made. 

Even though these drugs show enormous potential for NDD treatments, there is still a long way to go until such medicines can become commonplace. First, RNA tends to degrade in a cell relatively quickly [17, 18]. A drug made of RNA must be able to survive in the body long enough to enter the cells or organs of interest and interact with other molecules. To combat this degradation, the RNA is often packaged in lipid nanoparticles, which are spheres made of lipids (a type of fat molecule). Second, these treatments are somewhat invasive. RNA-based medicine cannot be taken orally; the technology still hasn’t developed to that point of convenience. For treatment to be effective, it needs to be injected either subcutaneously (under the skin) or intravenously (into the bloodstream). Third, there are potential side effects of RNA medicines, many of which we may not know of yet. For example, intotersen can lower one’s blood platelet count, potentially leading to difficulty in clot formation and, therefore, severe bleeding. Additionally, patients who receive patisiran also need to receive steroids to suppress other unwanted infusion-related reactions [17]. As such, researchers are still trying to uncover the consequences of, or risks associated with, RNA-based medicines. 

RNA: The Future of Medicine?

RNA may be useful in the treatment of NDDs and other physiological diseases. In fact, the COVID-19 pandemic may be accelerating RNA-based research, as both the Pfizer and Moderna vaccines are mRNA vaccines [19]. When you get either vaccine, you are injected with mRNA that codes for all or part of the spike protein found on the surface of SARS-CoV-2 (i.e. the virus that causes COVID-19) [20]. Your immune cells then manufacture that very protein, and its presence triggers an immune response. Then, if you are infected with SARS-CoV-2 following your vaccination, the immune system will already be equipped with the ability to handle the virus quickly before it can cause any serious damage [20]. Arming the immune system with preemptive knowledge of a disease is the basic premise of vaccines. However, some vaccines accomplish this using a different strategy. The Sinopharm vaccine created by the Beijing Institute of Biological Products, for example, uses a handicapped version of the actual SARS-CoV-2 virus to reach immunity [21]. NDDs are very different from viral infections, but the success of these RNA vaccines coupled with increased research behind RNA’s roles in NDDs still may lead researchers to develop RNA-based medicines for NDDs [22]. 

Despite expectations of RNA acting solely as a messenger (or a copier of recipes), recent research has proven it to be a molecule of many trades. With its diverse classes and forms, RNA is a multifaceted player in many essential neural processes. Considering the increasing prevalence of NDDs, discoveries of neurodegenerative implications associated with RNA-mediated protein production are more imperative than ever. While we still have a lot to learn about RNA’s role in the process of neurodegeneration, RNA-based medications offer a promising new treatment option to the millions of people suffering from NDDs and may be the first step taken toward finding a cure.

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