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

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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A Combined Approach to Treatment: Targeting PAKs in SCA1

Written by Carrie A. Sheeler  Edited by Dr. Marija Cvetanovic

Group 1 p21-associated kinases (PAKs) present a new avenue for SCA1 research.

Spinocerebellar ataxia type 1 (SCA1) is caused by a specific mutation in the Ataxin1 gene, which causes the protein that’s made from that gene (also called Ataxin1) to have an abnormally elongated polyglutamine (polyQ) tract. This leads to dysfunction and death in the affected cells of the brain (predominantly Purkinje neurons in the cerebellum), which causes symptoms in patients that include a progressive worsening of coordination and balance. While there is currently no cure for SCA1, several studies suggest that lowering the amount of Ataxin1 protein in the brain may delay the onset of the disease and decrease the severity of symptoms. This leads us to an important question: how do we most effectively decrease the amount of Ataxin1 in SCA1 patients? One paper recently published by Bondar and colleagues suggests that a multi-pronged approach could be the most effective means of reducing this toxic protein.

close up of two people shaking hands
Evidence suggests combining two potential treatments has a greater impact than each treatment on its own. Photo by on

The amount of any specific protein in the body can be altered by either decreasing the amount of protein produced or increasing the rate at which cells break those proteins down. Proteins are made using messenger RNA (mRNA), which is created following specific instructions found in DNA. Decreasing the production or stability of mRNA decreases the amount of corresponding protein made. One way to target the mRNA that causes production of a specific protein is with antisense oligonucleotides (ASOs). ASOs are designed to target specific mRNA sequences by binding to them directly. Binding of ASOs to mRNA causes those molecules to be marked for destruction within the cell. Proteins in the body are also regularly recycled, but without the blueprints to build a new protein, cells cannot replenish the protein supply it loses over time. So, if Ataxin1 mRNAs are targeted and destroyed by ASO treatment, the amount of Ataxin1 in our cells would theoretically decrease.

Some proteins can also be altered by other proteins, creating another way that their stability, shape, and function can be regulated. This leads us to the other way we can alter the amount of a specific protein in a cell: regulating the regulators. In terms of SCA1, this could mean removing a protein that helps stabilize Ataxin1 or increasing the production of a protein that breaks Ataxin1 down. Previous research has identified several proteins of interest that regulate Ataxin1 protein stability, including several kinases. Kinases are a class of proteins that transfer a phosphate group from adenosine triphosphate (ATP) to another protein in the cell. The addition of this phosphate group acts as an energy source to the receiving protein, altering its stability or how it interacts with other molecules in the cell (usually by causing it to change its shape). Recently, Bondar and colleagues have identified a new potential regulator of Ataxin1: a group of proteins known as p21-activated kinases (PAKs) (Bondar et al 2018).

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Blurred lines: how spinocerebellar ataxia type 7 impacts vision

Written by Siddharth Nath Edited by Dr. Ray Truant

Spinocerebellar ataxia type 7 (SCA7) is unique amongst the SCAs in that it involves an organ besides the brain – the eye. Rather than problems with movement, the first hint that something may be wrong for SCA7 patients is often a subtle change in vision. Research done by Dr. Al La Spada in the early 2000s helps explain how and why this happens. 

It’s not all in your head

The spinocerebellar ataxias (SCAs) are, for the most part, similar in how they affect the body. They cause disordered movement (ataxia), trouble with speech (dysarthria), trouble swallowing (dysphagia), and other neurological symptoms. This holds true for all of the polyglutamine-expansion SCAs except for SCA7. In SCA7, doctors have long observed that patients report problems with vision, and in some cases may be entirely blind. Interestingly, these symptoms often appear ahead of any other signs that the patient might have a chronic illness, suggesting that SCA7 affects the eye before it begins to affect the brain.

In the early 2000s, while at the University of Washington, Dr. Al La Spada conducted research into how SCA7 affects the eye. He and his team set out to understand why patients with this disease experience a loss of vision.

Close up photo of a human eye from the side. The eye is hazel in colour.
Close up of a human eye. Photo by Pixabay on

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Mitochondrial Dysfunction Found in SCA1 Purkinje Cells

Written by Dr. Terri M Driessen Edited by Dr. David Bushart

Mitochondrial dysfunction and loss of mitochondrial DNA is identified in an SCA1 mouse model.

Spinocerebellar ataxia type 1 (SCA1) is a neurodegenerative disorder that causes cell death in certain parts of the brain. The brain regions affected play important roles in motor coordination. The loss of coordination and movement – a symptom called ataxia – is the one of the primary effects of this disease. To investigate the causes of SCAs, researchers often use mouse models. In mouse models of SCA1, there are deficits in motor coordination before a significant amount of neurons (i.e., brain cells) are lost. This suggests that changes in neuron function, and not necessarily neuron death, may cause behavioral changes in SCA1. However, the mechanisms that cause dysfunction in SCA1 neurons are still a mystery.

Diagram of neuron, highlighting the nucleus, cytoplasm, golgi apparatus, membrane, mitochondria, microtubules, myelin sheath, lysosome, smooth ER, rough ER, dendritic spines, and dendrite.
Image courtesy of Blausen Medical on Wikimedia Commons.

The brain requires a lot of energy to function. Without this energy, our neurons would be unable to survive. The cellular machines that generate this energy are the mitochondria, which are small organelles found in neurons (and nearly every other type of cell, for that matter). If the mitochondria in neurons do not function properly, this could lead to abnormal neuronal functioning. In fact, mitochondrial dysfunction has been found in several neurodegenerative diseases, such as Amyotrophic Lateral Sclerosis (ALS, or Lou Gehrig’s disease), Spinal Muscular Atrophy, Alzheimer’s Disease, Parkinson’s Disease, and Huntington’s Disease. Previous studies have also linked mitochondrial dysfunction to SCA1. It has been shown that Purkinje cells, the major cell type affected in SCA1, have altered levels of mitochondria-related RNA and proteins in SCA1 mouse models (Stucki, et al. 2016; Ferro, et al. 2017).

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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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