Huntington’s disease : It’s all about the balance …

It’s in your genes.

You have probably heard people telling you that: “It’s in your genes”! Most likely, they were talking about a physical characteristic, a personality trait, or a specific talent that you share with other members of your family. We know that genes play important roles in shaping how we look and act and even whether we develop illnesses. For example, there are genes that increase the risk of you getting sick. Scientists have revealed some of them, while others still remain unknown.

Genes are made of deoxyribonucleic acid (DNA) and carry our traits through generations. Every cell in our body, except for our red blood cells and some cells in the skin, hair, and nails, carries a long string of DNA that tells the cell how to produce proteins. The DNA is like a cook book full of recipes with very exact instructions on how to put together proteins. These recipes are based on the way that the different components of the gene, represented by the four letters of “A”, “T”, “C” and “G” are organized throughout the gene. This means that the different ways of organizing these letters will lead to different proteins. The resulting proteins are the workhorses of our body. They play crucial functions inside the cells and are required for maintaining the structure, function and regulation of the body’s tissues and organs.

Typos in the DNA of HD patients

Occasionally, there are typographical errors in the DNA sequence. This mistake, which can be a change of building blocks in the form of gaps or duplications, is called a mutation. A mutation can cause a gene to make a protein that works incorrectly or that doesn’t work at all. Huntington’s Disease (HD) is a good example of a disease caused by a mutation. HD results from a single type of mutation in a given position of a single gene called the huntingtin gene. The mutation consists of three building blocks, “C A G”, that are repeated in a long stretch in the DNA.

We all have that same size stretch of “CAG” in the DNA, but the length varies from individual to individual. In HD, this stretch of DNA is abnormally too long and ends up making a long and bulky protein that the brain doesn’t like! This mutation was discovered in 1993 and ever since, scientists have tried to answer why individuals develop this brain disease as a result.

The good and the bad protein

Just like there are good and bad types of fat, there are good and bad types of proteins; In the case of HD, a protein is generated through reading of the recipe from the abnormally long CAG stretch in the DNA. This protein is harmful to our brain cells. Typically, a person would develop HD if he/she inherits one single bad copy of the gene from one parent, regardless of whether the other copy of the gene from the other parent is healthy or not (Genetics 101 review: you always inherit two copies of each gene, one from your mom and one from you dad!). In other words, one faulty version of the huntingtin gene is enough to cause trouble.

Normally, the symptoms of HD don’t present themselves before the person who carries the gene reaches adulthood. The age at which the person develops the disease depends on the length of the CAG in his/her DNA sequence. The longer the sequence, the earlier the person starts manifesting the disease symptoms. However, symptoms of the disease and the onset can vary between individuals despite having the same length of the CAG repeat. This has led scientists to wonder about what other factors might be at play.

The push-button dimmer switch that controls the huntingtin gene

Recently scientists have found an important change in the DNA just outside of the huntingtin gene in a region called the promoter. The gene promoter is like a push-button dimmer switch that can be turned on and off to control how a gene codes for a protein. Similar to when you push the smooth button to switch lights on/off, and rotate to adjust the light level up or down, promoters determine the level of protein that is produced through the expression of genes.

dimmer switch


Researchers have found that the change in the promoter of the huntingtin gene is enough to control gene expression. In fact, if this recently-discovered change is present, there is always less expression of the gene segment that follows.

Remember that HD patients often ‘carry’ one normal and one abnormal copy of the huntingtin gene (instead of two normal copies or two abnormal copies). The scientists showed that HD patients with the change in the promoter on the normal copy of the huntingtin gene always made less of the good protein that is protective of the brain. As a result, these patients developed motor symptoms on average 4 years earlier than patients without the change in the DNA!

Interestingly, the HD patients with this change on the promoter of the abnormal copy of the huntingtin gene also made less of the harmful protein that is toxic to the brain. These patients developed motor symptoms on average 10 years later compared to patients without this change!!

This study reveals important information on how small changes in the DNA candetermine the time of disease onset by affecting the balance between the good and the harmful protein.

Depiction of chromosome #4 contains the huntingtin gene in people. The figure shows how CAG repeat mutation in this gene can lead to HD and how an extra change in the nearby DNA can lead to earlier or later onset in patients with similar repeat size.

Depiction of chromosome #4 contains the huntingtin gene in people. The figure shows how CAG repeat mutation in this gene can lead to HD and how an extra change in the nearby DNA can lead to earlier or later onset in patients with similar repeat size.

What’s next?

This is the first time a study has described a change in the huntingtin gene that acts as a push-button dimmer switch controlling how much huntingtin protein is made. In addition, this change is shown to determine a more realistic estimate of the time when the patient develops the disease.

We previously talked about “Gene Silencing” as a potential therapeutic method for HD. The dimmer buttons such as the one described here can be used toward designing an effective gene silencing strategy in which the bad protein is reduced. Studies suggest that turning off both the good and the bad protein might delay symptom onset, but that keeping the good protective protein and only turning off the bad protein, might turn out to be a more effective therapy.

This research study presents the importance of the balance between the good and the bad huntingtin protein – where the net balance drives the onset of motor symptoms in HD in one or the other direction.

Scientists will now be able to use the knowledge gained from this study in exciting new ways, most importantly in the efforts to find more “dimmer buttons” and in the development of novel therapies for HD.

Editor’s note: Dr. Bečanović has given a talk about this work and HD in general. See her great lecture as a Youtube video:


Study:  Kristina Bečanović, Anne Nørremølle, Scott J Neal, Chris Kay, Jennifer A Collins, David Arenillas, Tobias Lilja, Giulia Gaudenzi, Shiana Manoharan, Crystal N Doty, Jessalyn Beck, Nayana Lahiri, Elodie Portales-Casamar, Simon C Warby, Colúm Connolly, Rebecca A G De Souza, Sarah J Tabrizi, Ola Hermanson, Douglas R Langbehn, Michael R Hayden, Wyeth W Wasserman, Blair R Leavitt. A SNP in the HTT promoter alters NF-κB binding and is a bidirectional genetic modifier of Huntington disease. Nature Neuroscience, 2015; DOI: 10.1038/nn.4014

Rate it:

1 Star2 Stars3 Stars4 Stars5 Stars (No Ratings Yet)