A Creatine-rich Diet Delays Disease in SCA3 Mice

Written by Dr. Lauren R. Moore Edited by Larissa Nitschke

Creatine, a common dietary supplement taken by athletes, delays symptoms and improves balance and strength in SCA3 mice.

Could a common nutritional supplement used by athletes to boost performance also provide benefits to ataxia patients? This was the main question addressed by a recent study of Spinocerebellar Ataxia Type 3 (SCA3), the most common dominantly-inherited ataxia in the world. The study, published in March 2018, was led by Dr. Sara Duarte-Silva at the University of Minho in Portugal. Dr. Duarte-Silva and her team investigated whether feeding SCA3 mice a diet enriched with creatine – a popular dietary supplement – improves the symptoms and brain changes that are associated with SCA3. Researchers found that a high-creatine diet delayed disease and slowed the worsening of symptoms in SCA3 mice. This study provides promising evidence that increasing or adding creatine in daily consumption may have protective benefits for SCA3 patients.

SCA3 is one of six hereditary ataxias caused by a unique type of genetic mutation known as a CAG trinucleotide repeat expansion. This occurs when a repeating sequence of three DNA nucleotides – Cytosine-Adenine-Guanine or “CAG” for short – is expanded, creating an abnormally high number of repeats. In SCA3, mutation occurs in a gene encoding the protein ATXN3 and produces an abnormally long “sticky” region in the disease protein. This sticky region, called a polyglutamine expansion, impairs ATXN3’s normal functions and causes it to build up in brain cells as toxic protein clumps. As a result, the brain’s ability to make and store energy is often impaired in SCA3 patients (a deficit that is also seen in many other brain disorders). Thus, drugs or compounds that improve overall energy production and use in brain cells could be beneficial in SCA3 and other ataxias.

man with white pill in his hand
Photo by rawpixel.com on Pexels.com

One such compound that may increase energy efficiency – particularly in the brain and muscles – is creatine. Creatine is made naturally by the body, but can also be consumed through foods like red meats and seafood. In addition, creatine is a common ingredient in many commercially-available dietary supplements that claim to improve athletic performance by boosting energy and building muscle. Creatine has recently been shown to have some benefits in mouse models of other brain diseases with similarities to SCA3. However, whether creatine could benefit SCA3 patients hadn’t been investigated prior to this study.

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Connecting genetic repeats to symptom variability in SCA3/MJD

Written by Terry Suk Edited by Dr. Hayley McLoughlin

In this classic article, researchers describe how CAG repeat number variation can inform differences in the way SCA3/MJD symptoms present.

Machado-Joseph Disease (MJD) was first described in the 1970’s in four families of Azorean descent. However, it was not initially clear that these families had the same disease, since the symptoms they displayed were highly variable. These symptoms included differing degrees of motor incoordination, muscular atrophy (i.e., loss of muscle mass), spasticity, and rigidity. Later, these four diseases were labeled using the single title of MJD due to their similar genetic inheritance and irregularly high symptom variability1.

In the early 1990’s, a group of French families were diagnosed with Spinocerebellar Ataxia Type III (SCA3), a disease that appeared similar to SCA1 and SCA2 but was shown to be caused by distinct genetic mutation. The symptoms of SCA3 were similar to those of MJD and, importantly, also showed a high degree of variability. The major differences between the two diseases, however, were mostly based on geographical origin (Azorean versus French descent) and family history. Thus, these were considered separate diseases, and very few (if any) ataxia researchers studied both.

Small human figurine standing on a map of the world, specifically on top of France
Initial research done by Cancel and colleagues focused on four French families. Photo by slon_dot_pics on Pexels.com

Then, in 1994, MJD-1 was discovered to be the gene responsible for MJD. The disease-causing mutation in MJD-1 was found to be an expansion of a repetitive DNA sequence in the gene, described as “CAG repeats” (CAG = Cytosine, Adenine, and Guanine)2. Around this time, another research group narrowed down the location of the gene responsible for SCA33. Interestingly, this happened to reside in the same area of the genome as MJD‑1, which was appropriately named the “SCA3/MJD region” soon after. As mentioned above, both SCA3 and MJD patients displayed a wide variety of symptoms. This lead one group of researchers, Cancel and colleagues, to ask the following question in their 1995 publication: What is it about the SCA3/MJD region that leads SCA3 and MJD patients to exhibit such broad symptomatic variability?

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Where Should We Look to Detect SCA3 Pathology and Progression?

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).

Textbook diagram of brain
Diagram of the human brain. Picture courtesy of Internet Archive Book Images

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).

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A novel therapeutic approach for the treatment of SCA3

Written by Larissa Nitschke Edited by Dr. Gülin Öz

Researchers in the Netherlands uncover a new way to treat SCA3

Upon receiving a conclusive diagnosis of Spinocerebellar Ataxia (SCA), hundreds of questions can appear in a patient’s mind: What is Spinocerebellar Ataxia? Why am I affected? How will my symptoms progress? What is the ultimate prognosis? Thankfully, years of research have enabled us to answer many of these questions for patients affected by Spinocerebellar Ataxia Type 3 (SCA3), also known as Machado-Joseph Disease. Still, the most important question a patient could ask – How can I be healthy again? – has remained unanswered.

SCA3 is the most common form of Spinocerebellar Ataxia worldwide. It is passed down from generation to generation in affected families. Initial symptoms typically appear around midlife, but cases of much earlier and much later onset have been reported. At first, problems with movement coordination are the most noticeable, leading to an increase in stumbles and falls. At later stages, speech difficulties, muscle stiffness, and sleeping problems appear, leaving the patient fatigued during the day. The symptoms worsen over the course of 10 to 20 years, at which point affected individuals typically succumb to the disease. As with other SCAs, current options for SCA3 treatment are mainly limited to symptom management rather than treating the direct cause of the disease.

Artist's representation of DNA
Artist’s representation of DNA. Photo from Pixabay.

The genetic cause of SCA3 is the presence of excess copies of the DNA building blocks cytosine (C), adenine (A), and guanine (G) in the Ataxin-3 gene (Atxn3). Scientists refer to this type of mutation as an expansion of a triplet repeat, since the C, A, and G copies appear as sets of back-to-back CAGs. Because the CAG triplet is responsible for coding the amino acid glutamine (Gln or Q) in the Ataxin-3 protein, the repeat expansion results in an elongated glutamine (polyQ) tract. This faulty protein accumulates in cells and causes toxicity in specific regions of the brain. Since the 1994 discovery that SCA3 is caused by a polyQ expansion in Atxn3, scientists and physicians all over the world have been humbled by the question of how to help patients affected with SCA3. One specific angle of research has focused on the removal of the toxic protein altogether. However, one downside of this approach is that it would also cause the loss of normal Atxn3 function in patients. Atxn3 is critical for the degradation of unwanted proteins, which is necessary for the healthy functioning of all our body’s cells. It normally binds to little marks on proteins called ubiquitin chains (which tag proteins for removal), then cleaves these chains to facilitate the entry of proteins into the cell’s destruction machinery. Since treatment will need to be sustained over the span of a patient’s lifetime, the complete removal of Atxn3 might be harmful.

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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.

dna-2358911_1280
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.

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