Written by Jorge Diogo Da Silva Edited by Dr. Maria do Carmo Costa
Potential drug targets and biomarkers of SCA3/MJD revealed
Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease (MJD), is a debilitating neurodegenerative disease that usually begins in mid-life. The mutation that causes SCA3 leads to the production of an abnormally large stretch in the gene’s encoded protein, ataxin-3. This irregular ataxin-3 becomes dysfunctional and starts to bundle into toxic aggregates in the brain. SCA3 patients experience a lack of movement coordination, especially when it comes to maintaining their balance while standing or walking, which worsens over time. Currently, there is no cure, effective preventive treatment, or method of monitoring the progression of SCA3. While finding a treatment for SCA3 is undoubtedly needed, identifying markers that are only present in individuals that carry the SCA3 mutation is also critical – it allows researchers and clinicians to track how the disease is progressing, even if the carriers do not show disease symptoms. The use of disease markers is especially important in evaluating the effectiveness of a therapeutic agent during the course of a clinical trial (in this case, one that includes pre-symptomatic carriers).
The protein ataxin-3 plays many roles in cells, including in transcription – the process by which genes (made of DNA) are transformed into RNA, which in turn encodes all the proteins that are essential to maintaining normal body function. Because the abnormally large ataxin-3 is somehow dysfunctional in SCA3, accurate transcription of genes could be affected. Hence, the authors of this study have looked at transcription in several brain regions in a mouse model of SCA3. These mice harbor the human mutant ataxin-3 gene in their DNA and replicate some of the symptoms that patients experience. In general, this kind of investigation can help provide clues for potential therapeutic strategies, which could work by normalizing the transcription of disease-affected genes. In addition, it can allow researchers to better characterize SCA3-affected genes, which could be used to monitor disease progression if one or more of these genes are affected differently at different stages of the disease. The authors also searched for potential dysregulation of other molecules in the blood of these mice, such as sugars and fats, which is another way disease progression could be monitored. This is particularly useful for patients, as a blood test is much less invasive than any kind of brain analysis. Here, researchers tested blood samples of mice at different ages, as well as brain samples from 17.5-month-old mice (roughly equivalent to a 50-year-old human).
Gene transcription was evaluated in four brain regions: cerebellum (the region most associated with maintenance of balance), brainstem (the region that connects the spinal cord to the brain), striatum (one of the innermost parts of the brain) and cortex (the main part of the brain). Compared to normal mice, the authors found hundreds of genes whose transcription was changed in the brainstem and striatum of SCA3 mice; in the cerebellum and cortex, they found less than 20. In addition, they found six genes that were dysregulated in all the tested brain areas of the SCA3 mice. The most dysregulated of these genes were found to be involved in the production of cholesterol, as well as in cellular signals to correct brain development.
As for the blood tests, the genes whose transcription was altered in SCA3 mice were mostly related to energy production. Mouse blood tests of sugars, fats and amino acids (the building blocks of proteins) were carried out at 3 different ages in the SCA3 mice (roughly equivalent to 20, 35 and 50 years of human age). The amino acid tryptophan and certain fat molecules were identified as potential markers of SCA3 in the blood, as their levels were altered in samples from SCA3 mice compared to normal mice. Blood tests measuring fat could be particularly interesting, as these showed different patterns at different ages. This suggests that fat molecules in the blood could be useful in differentiating stages of disease. Previous work has shown that these specific fat molecules have essential functions in the brain and are dysfunctional in a variety of neurological diseases, strengthening the case that they might be important biomarkers for SCA3.
But the important question here is: how can we use these findings to help patients?
On one hand, this study has provided clues to the scientific community about where to look for markers of SCA3. These findings are helpful to address a number of questions. Which processes can we target with drugs to improve brain function? If we want to tackle transcription, which genes should we address first? Where in the brain is gene transcription mostly affected? This work has helped answer some of these: it has shown that transcription is more affected in some brain regions compared to others, it has identified some of the genes that are affected in SCA3, and it has investigated the functions that are associated with these genes. Future research can now be prioritized to these genes and/or cellular functions, as they show the most abnormal levels in the disease – indicating that normalizing these altered processes might be a strategy to develop a treatment for SCA3.
Moreover, looking for ways to predict when symptoms of SCA3 will start is important for the lives of many patients and carriers, as it weighs on the decisions they/their doctors will make to manage the disease. Because this study identifies molecular markers that could possibly be used to monitor different stages of the disease using a simple blood test, it has important implications for strategizing patient care. Measurement of tryptophan and several fats in the blood are promising tests that might differentiate earlier stages of disease from more advanced stages.
In conclusion, these discoveries have brought us closer to an answer for the question “where should we look to detect SCA3 pathology and progression?” Though these findings are bolstered by previous research, it is now very important that the experiments in this study are conducted in different mouse models of the disease, by different research groups, and with different experimental conditions. That way, we can confirm that the promising markers of SCA3 identified here are as strong as they appear.
SCA3/MJD: a hereditary neurological disorder that becomes evident in mid-life. Main symptoms are the loss of balance while standing and walking, as well as a lack of motor coordination.
Transcription: the biological process in all living organisms by which the genetic information coded in DNA (in the form of a gene) is used to generate proteins, which are essential in carrying out all the functions of our cells. This process happens in nearly every cells of every organism, at all times, and in every stage of life.
Tryptophan: an amino acid. Proteins are made of several amino acids in a sequence. Tryptophan is an essential amino acid, which means that the human body cannot produce it. Therefore, it has to be acquired from food (proteins in the food are digested into its individual amino acids, one of which is tryptophan).
Conflict of Interest Statement
The authors and editor declare no conflict of interest. Dr. van Roon-Mom, the senior author of the article reviewed, is a contributor to SCAsource. They were not involved in the writing or editing of this piece.
Citation of Article Reviewed
Toonen, L.J.A., et al., Transcriptional profiling and biomarker identification reveal tissue specific effects of expanded ataxin-3 in a spinocerebellar ataxia type 3 mouse model. Molecular Neurodegeneration, 2018. 13: 31. (https://www.ncbi.nlm.nih.gov/pubmed/29929540)