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.

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.

The goal of the study from Bettencourt and her colleagues was to identify genetic factors that might influence the age of disease onset among polyglutamine diseases. To do so, they used a methodology known as a genome-wide association study, commonly referred to as a GWAS. To conduct a GWAS, scientists analyze the genetic information of a large number of patients to find single nucleotide polymorphisms, or SNPs (pronounced “snips”), that are associated with age of disease onset. SNPs are variations in a single nucleotide within a DNA sequence; for instance, a C may be replaced with a T. If these SNPs occur within a gene, they may affect gene function; likewise, if this gene’s function is important in disease development, it may affect when a patient develops disease symptoms and how severe those symptoms are. By looking at a large pool of patient genetic information, a GWAS study allows scientists to identify genes that are typically associated with an increased or decreased age of disease symptom onset.

For this study, the genetic information from over 1000 patients with different SCAs or HD were analyzed. Instead of looking at all possible genes for SNPs, the scientists chose to look at a smaller group of genes: those that are involved in DNA repair pathways. This is because DNA damage repair was identified as an important factor associated with age of HD symptom onset in another recent GWAS report (Genetic Modifiers of Huntington’s Disease (GeM-HD) Consortium, 2015). Cells experience tens of thousands of incidences of DNA damage every day. This damage can be due to environmental causes (i.e., ultraviolet radiation from the sun, which can cause a sunburn) or everyday cellular activities. To repair this damage and maintain the integrity of the cell’s blueprints, cells have dedicated machinery that is constantly working to repair and maintain DNA. Unfortunately, in some situations, DNA repair machinery can run amok, leading to additional problems at the DNA level. One such problem is known as “somatic expansion,” which can occur when DNA is repaired in the region of the CAG repeat (López Castel, Cleary, & Pearson, 2010; McMurray, 2010). Expanded CAG repeats have a tendency to take on unusual shapes. This can cause DNA repair proteins to act abnormally, resulting in further expansion of the CAG repeat (Iyer, Pluciennik, Napierala, & Wells, 2015; McMurray, 2010).

In the small pool of DNA repair genes analyzed, researchers found two genes (FAN1 and PMS2) that were associated with age of symptom onset for HD and the SCAs. An additional gene, RRM2B, was found to be specifically associated with the age of symptom onset in SCA6 and HD. Notably, all of these DNA repair genes were previously found in the HD GWAS (Genetic Modifiers of Huntington’s Disease (GeM-HD) Consortium, 2015), which tells researchers that DNA repair may be an important, common factor in both the SCAs and HD.

The main take-away from this study is that it appears that DNA repair pathways affect age of disease symptom onset in a number of polyglutamine diseases, suggesting that there may be more similarities between these diseases than we previously thought. DNA damage repair may be a common mechanism at play in the development of both SCAs and HD. This new information fits well with recent research in HD, which shows increased levels of DNA damage in HD patient cells (Askeland et al., 2018). This is a fairly new idea for the field of polyglutamine diseases, and suggests new, exciting research avenues to pursue. Besides giving scientists greater insight into how these diseases develop, there are also two practical implications of this work. The first is that the identification of this new pathway provides new information for therapeutic development that may be applicable to all polyglutamine diseases. The second is that, by identifying factors associated with variability in age of symptom onset, scientists will be able to improve clinical trial design. Both of these outcomes serve to increase the likelihood of developing effective disease treatments. Although the results of this study are exciting, it is important to note that they only suggest important new disease pathways to explore among the polyglutamine diseases; researchers will still need to figure out how DNA repair pathways influence polyglutamine diseases and whether it is something that can be targeted by therapeutics.

Key Terms

DNA : A molecule that contains the genetic code of an organism, used as a blueprint for making proteins.

Gene: A unit of heredity made up of DNA that fully or partially controls the development of specific traits.

Age at onset: The age at which an individual starts to develop symptoms of a disease.

Genome-wide association study (GWAS): An observational study of genetic variants, called SNPs, to identify SNPs that are associated with a trait (such as disease onset).

Single Nucleotide Polymorphism (SNPs): A variation in a single base-pair of DNA.

Conflict of Interest Statement

The author and reviewer declare no conflict of interest.

Citation of Article Reviewed

Bettencourt C., et al., DNA Repair Pathways Underlie a Common Genetic Mechanism Modulating Onset in Polyglutamine Diseases. Annals of Neurology, June 2016. 79(6): p. 983-90. (https://www.ncbi.nlm.nih.gov/pubmed/27044000)

References

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López Castel, A., Cleary, J. D., & Pearson, C. E. (2010). Repeat instability as the basis for human diseases and as a potential target for therapy. Nature Reviews. Molecular Cell Biology, 11, 165.

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Tezenas du Montcel, S., Durr, A., Bauer, P., Figueroa, K. P., Ichikawa, Y., Brussino, A., … Stevanin, G. (2014). Modulation of the age at onset in spinocerebellar ataxia by CAG tracts in various genes. Brain: A Journal of Neurology, 137(Pt 9), 2444–2455.

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Zoghbi, H. Y., & Orr, H. T. (2000). Glutamine repeats and neurodegeneration. Annual Review of Neuroscience, 23, 217–247.