Snapshot: What is Polyglutamine Expansion?

The information that allows the normal development and functioning of each human being is coded in DNA, which exists in all cells of the body. Several successive segments of DNA make up a gene, with the human body containing approximately 20,000. Every gene has a different arrangement of DNA segments and itself codes for a protein with a specific function. Genes code for proteins in the sequence of their DNA: combination of DNA sequences “code” for different protein precursors called amino acids. Thus, information from DNA (“genes”) codes for amino acids, which come together to form proteins, who function to maintain the normal well-being of the body.

A small number of genes have a small segment of DNA that is repeated successively, usually a couple dozen times, for unknown reasons. When the respective protein is formed, it also possesses a repetition of the same amino acid, corresponding to the repeated DNA segment. These repetitions in proteins have the prefix “poly”, meaning that the amino acids are repeated multiple times in a row, causing an “expansion” in the protein. One of the most common repeated amino acids is called glutamine: hence the name, polyglutamine.

Diagram showing how multiple CAG triplet repeats code for replicates of glutamine to be inserted into a protein
Photo courtesy of NHS HEE Genomics Education Programme.

When there is an increase in the number of repetitions of these segments in DNA, we say that an expansion of the polyglutamine has occurred. When the number of glutamines is increased sufficiently, a disease can develop: we call these disorders “polyglutamine diseases”. Some examples of diseases caused by this polyglutamine expansion are Huntington’s disease, SCA1, SCA2, SCA3, SCA6, and SCA7. The difference between all these diseases is that the expansion of the DNA segment that causes the polyglutamine occurs in different genes. Since these genes are distinct, the way that this expansion interferes with the normal body functioning is also different, giving rise to altered clinical presentations and courses. Moreover, it has been well established that, the larger the number of times that the segment is repeated, the more severe the disease will be. Finally, it has also been observed that throughout each generation, abnormally increased segments tend to become even bigger, making the disease worse.

The discovery of this mechanism of disease has been very important for scientists, since it allows for a “molecular diagnosis” of the disease. Armed with this understanding, research is now focused on understanding this process and finding ways to block the negative effects of polyglutamine expansion.

If you would like to learn more about polyglutamine expansion, take a look at this article.

Snapshot written by Jorge Diogo Da Silva, edited by Dr. Maxime Rousseaux

 

 

DNA Damage Repair: A New SCA Disease Paradigm

Written by Dr. Laura Bowie Edited by Dr. Hayley McLoughlin

Researchers use genetics to find new pathways that impact the onset of polyglutamine disease symptoms

The cells of the human body are complex little machines, specifically evolved to fulfill certain roles. Brain cells, or neurons, act differently from skin cells, which, in turn, act differently from muscle cells. The blueprints for all of these cells are encoded in deoxyribonucleic acid (DNA). To carry out the instructions in these cellular blueprints, the DNA must be made into ribonucleic acid (RNA), which carries the instructions from the DNA to the machinery that makes proteins. Proteins are the primary molecules responsible for the structure, function, and regulation of the body’s organs and tissues. A gene is a unit of DNA that encodes instructions for a heritable characteristic – usually, instructions for a making a particular protein. If there is something wrong at the level of the DNA (known as a mutation) then this can translate to a problem at the level of the protein. This could alter the function of a protein in a detrimental manner – possibly even rendering it totally non-functional.

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Artist representation of a DNA molecule. Image courtesy of gagnonm1993 on Pixabay.

DNA is made up of smaller building blocks called nucleotides. There are four different nucleotides: cytosine (C), adenine (A), guanine (G), and thymine (T). Polyglutamine diseases, such as the spinocerebellar ataxias (SCAs) and Huntington’s disease (HD), are caused by a CAG triplet repeat gene expansion, which leads to the expansion of a polyglutamine tract in the protein product of this gene (MacDonald et al., 1993; Zoghbi & Orr, 2000). Beyond a certain tract length, known as the disease “threshold,” the length of this expansion is inversely correlated with age at disease onset. In other words, the longer this expansion is, the earlier those carrying the mutation will develop disease symptoms. However, scientists have determined that onset age is not entirely due to repeat length, since individuals with the same repeat length can have different age of disease symptom onset (Tezenas du Montcel et al., 2014; Wexler et al., 2004). Therefore, other factors must be involved. These factors could be environmental, genetic, or some combination of both.

Continue reading “DNA Damage Repair: A New SCA Disease Paradigm”