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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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



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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Snapshot: What is DNA?

DNA (deoxyribonucleic acid) is the way that living beings store the information that determines how they look and function. Think about DNA as the blueprints, or instructions, for life. All life forms – humans, cats, dogs, trees, and bacteria – all contain DNA. Your DNA is what carries the information that decides your specific traits, like what color eyes you have or if you will be tall or short. All the information in your DNA is unique to you. No one else in the world has the exact same DNA as you, unless you have an identical twin. You do share about fifty percent of your DNA with your biological parents, because the information stored in DNA is transmitted from generation to generation. This is why you look a little bit or a lot like your parents.

The reason that traits, like having blue eyes or being short, run in families is because they are transmitted in genes, which are the functional units of DNA.  Genes work on a very small scale, providing instructions to the cells of your body so they know what they need to make to do their jobs. While normal changes in the DNA can influence physical characteristics, like eye color, sometimes abnormal changes in the DNA may cause individuals to develop a disease. This is the case for hereditary ataxias. The abnormal DNA changes (called “mutations”) make it so cells no longer do their jobs well. Although we live with the same DNA information all our lives, it may take years or decades for a disease to manifest. As with genes for eye color, the genes causing a disease can be transmitted across generations. This explains why families are more likely to have relatives with the same type of ataxia.

Cartoon drawing of DNA moleculue next to an image of a ladder
Cartoon of DNA (Left), Photo of a ladder (right)

So, that is what DNA does, but what does it actually look like? DNA forms a double helix, think of it as a twisted ladder. The sides of the DNA ladder are made up of sugars, specifically “deoxyribose” units, and phosphate groups, and the rungs of the ladder are made up of bases. There are four bases, adenine, thymine, guanine, and cytosine, or A, T, C, and G for short. In the DNA ladder, each rung is made up of two bases forming a pair, either A and T or C and G. The instructions for life are “written” into our DNA using these bases, sometimes called the “genetic code”. The language of the genetic code has a lot fewer letters than our alphabet, just A, T, C, and G, but together these four bases write every instruction for every function and characteristic of every living thing that has ever existed in the form of genes.

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

Snapshot written by Dr. Laura Bowie, edited by Dr. Judit M Perez Ortiz.



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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