Today, we will once again talk about another disease. This time, we will focus on Huntington’s disease (or HD). HD is part of the neurodegenerative diseases and today, we will try to understand it and review some hypotheses that explain the disease development.

The symptoms of HD are classified in three groups. First, there are motor symptoms. The biggest one is called chorea, which means that the person will have a lot of involuntary movements. People with HD also have difficulty walking and talking, and have reduced coordination. There are also cognitive symptoms, the main one being increased memory loss, and loss of focus. It can even lead to personality changes. Lastly, there are more emotional symptoms, including anxiety, depression, and irritability. Like most neurodegenerative diseases, HD is a late-onset disease, meaning that symptoms appear quite late in the life of the patient, usually around 60 years old. This disease is very hard to diagnose before the symptoms appear, but early changes in personality such as abnormal mood swings could be a sign of HD, however the only accurate way to diagnose it is a DNA test. Unfortunately, there is no cure for the disease. There are medications to help reduce the symptom severity, such as haloperidol for the chorea, but to this date, nothing can stop the course of the disease [source / source / source].

As I just mentioned, HD is part of a group of disease called neurodegenerative diseases. This means that there is an impairment in neuronal function, which leads to loss of neurons over time. The loss of neurons is initially restricted to one area of the brain, but over time the entire brain is affected. There are many diseases that are neurodegenerative, including Alzheimer’s disease, Parkinson’s disease, and Creuzfeldt-Jacob disease (also known as the mad cow disease). Many things can cause the loss of neurons, but in the case of HD, it seems to be linked to a protein called huntingtin (HTT). This protein is still to this day a mystery, as we have no clear idea of its function. We know that it is an essential protein for development, since removing it in mice embryo causes its death. It is also important for neuronal survival, as reducing amount of HTT increases neuronal death. Other than that, its actual functions are unknown. We however know what it becomes during HD. People with HD get an overly large version of this protein, called the mutant huntingtin (or mHTT). The gene for the HTT protein contains a piece that can be repeated. In the HTT protein, this part is called a CAG repeat. When the gene is translated, this part of the gene is read multiple times, causing the protein to have multiple CAG repeats. This is happening in everyone and is harmless unless the amount of CAG repeats exceeds 40, then the person is diagnosed with HD. This is because with that many repeats, the protein is unable to function properly. Worse, it may develop new functions that accelerates neuronal death [source / source / source / source].

It is important to understand that while we know that the disease stems from mHTT, we still don’t know how the disease develops and what leads to neuronal death. There are many hypotheses however, and today I will explain three of them.

Hypothesis 1: mHTT aggregate and misfolding

To understand this hypothesis, it is important to know protein folding. when protein are created from gene translation, they are first just a line. However, the protein doesn’t stay a line and very quickly folds into a very specific configuration in order to perform its function. It happens however, that protein misfolds. In that case, the cell will get rid of it, since a misfolded protein can lead to many problems. Since mHTT is very different from HTT, the protein misfolds. However, for reasons still unknown, the neurons are unable to remove the protein, which leads to aggregation of misfolded protein. This theory is true to almost all neurodegenerative disease. However, in the case of HD, it is more controversial. While we do observe protein aggregates in both patients and animal models of HD, there is little link between the aggregation and neuronal death. It is likely that the aggregation isn’t causing neuronal cell death, but it somehow removes the ability to get rid of misfolded protein. And without this mechanism, the cell becomes stressed, which promotes its death. This however is just a hypothesis that was not proven [source / source].

Hypothesis 2: Mitochondrial dysfunction

Mitochondria are organelles found in most cells and provide essential roles for the cells. Many of us have heard it being called the powerhouse of the cell, and that’s because it creates the energy essential for cell function: ATP. ATP is used for most protein function, as well as any other cell mechanisms, and it is thanks to the mitochondria that we have it. However, in the case of HD, the mitochondria does not work as well as it should. Two mechanisms happen in neurons: first, the production of ATP is greatly decreased. this may lead to an increase of production of reactive oxygen species (ROS). ROS are products that are extremely toxic to the cell. Both patients and animal models have increased ROS, as well as signs of ROS-induced damages. However, we do not know if mitochondrial dysfunction is a cause or a consequence of HD [source / source / source].

Hypothesis 3: Excitotoxicity

This hypothesis is a bit more complex, but in short, neurons in HD may be excited to death. Neuronal excitation is the basis of brain function, and it is done thanks to proteins called neurotransmitters. Once a neuron comes into contact with specific neurotransmitters, it will open its membrane and a bunch of ions will enter. Ions have an electrical charge, and if a lot of positive ions enter, then the cell becomes more positive, or excited. However, too much of ions can be dangerous, especially if it is a calcium ion. Calcium ions are in extremely low amount in the cell, because it is also used to activate proteins. Now if a lot of calcium enters the cell, then some protein may be activated, which will lead to cell damage, and eventually cell death. This is excitotoxicity. In general, it is due to the neurotransmitter glutamate being too present, or its receptors having problems. In the case of HD, we hypothesized that there is a problem in one of glutamate’s receptor, called NMDA, and this leads to too much calcium entering the cell, leading to cell death via excitotoxicity. This hypothesis is however not proven yet [source / source / source].

We can see that HD is a very complex disease, but also a very mysterious one. While we know a lot about it, we are still missing key components in order to fit everything together. It is likely that every hypotheses that were shown are actually happening in HD patients, but what is the root of everything? What component is the cause for everything? This is why we continue to actively research this disease, because understanding it will help cure it.