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.

How we see

Before we dive into the La Spada lab’s findings about how SCA7 and mutant ataxin-7 protein damage vision, it is important to briefly discuss how our vision works. Our eyes are astounding organs that allow us to perceive the world in all its beauty and, though they are incredibly complex, can be understood as nature’s version of something we are all familiar with: a camera.

Like a camera, the eye has a clear window at the front – the cornea – which bends light coming into the eye. This light then passes through the pupil, which is the small dark hole in the center of the eye. Similar to the aperture of a camera, the size of the pupil can change based on how much light is in the environment: when it’s dark, our pupil enlarges to allow more light into the eye, and when our surroundings are bright, our pupil shrinks. This size change is controlled by a structure adjacent to the pupil called the iris. As light passes through the pupil, it then goes through a lens, which focuses the light onto the retina (located at the back of the eye). The retina acts like the sensor chip in a digital camera, which means that what we see is actually a pattern of light projected onto the retina. As light hits the retina, it activates specialized cells called photoreceptors. There are two types of photoreceptors: rods and cones. Cones are able to detect color (red, blue, and green, specifically) and are responsible for vision in conditions with lots of light. Rods, on the other hand, are responsible for our low light vision and do not detect color.

Together, these specialized cells convert light into electrical signals. These impulses then travel up through nerve fibers in the back of the eye behind the retina, through our skull, and into our brain. The brain’s job is to decode these messages, forming a coherent visual image from the signals. All of this is done incredibly quickly, allowing us to have sharp, precise vision. If you think about it, we really ‘see with our brain’ and not with our eyes. Our eyes are simply there to allow us to capture light from the environment and convert it into signals our brain can understand.

What goes wrong in SCA7

Dr. La Spada’s work, along with the observations of clinicians, suggests that vision loss in SCA7 occurs because of issues with the retina (the area at the back of the eye where an image is initially formed). In patients with SCA7, clinicians have observed degeneration of the retina, specifically in an area called the macula, which has a high concentration of specialized cone photoreceptor cells. This ‘macular degeneration’ is visible on a physical exam and usually presents as issues with discriminating colors and/or vision loss in the center of the visual field.

To understand what goes wrong in SCA7, Dr. La Spada created mouse models which aimed to replicate the disease. Working with his team of researchers, he developed mice which expressed ataxin-7, the protein affected in SCA7, with either 10Q (10 glutamines, a typical polyglutamine tract length) or 92Q (92 glutamines, which represents a polyglutamine expansion similar to what is seen in SCA7 patients). When examining retinal tissue from mice with the mutant 92Q protein under a microscope, researchers noted an increased number of dying cells. Researchers also used a specialized vision test called an electroretinogram (ERG) to measure the function of cones and rods in the SCA7 mice. Their ERG results showed that the disease induces a ‘cone-rod dystrophy,’ in which cone cells are affected prior to rods.

Next, the researchers sought to determine how this retinal degeneration was occurring. We know that ataxin-7 is involved in the regulation of multiple genes – i.e., determining the extent to which genes are turned on and off within the cell – so Dr. La Spada and his team looked to see whether mutant ataxin-7 was disrupting the activation or suppression of retinal-specific genes. After some pilot studies, they decided to look more closely at the gene that encodes cone-rod homeobox protein (CRX for short), which is another type of gene regulator known as a transcription factor. Dr. La Spada and his team found that CRX was present within aggregates of mutant ataxin-7 protein in the retinal cells of diseased mice. Using techniques to investigate protein interactions, they then observed that ataxin-7 and CRX can interact directly. Most importantly, they also found that these interactions are abnormal in SCA7.

What does this all mean?

Taken as a whole, these findings tell us that the mechanism behind retinal degeneration in SCA7 is the interference of CRX’s genetic control by the mutant ataxin-7 protein. This is important because it paves the way for us to consider potential treatments. Although degenerated retinal tissue cannot be restored, if we can develop a way to restore CRX function in SCA7, we may be able to prevent vision loss before it even begins. This paper is considered one of the most important in the field and serves as a crucial reference to this day.

Key Terms

Retina: The structure at the back (i.e., the innermost region) of the eye. The retina works like the film/digital sensor in a camera: light is focused onto it by other parts of the eye, and it converts this light pattern into a series of electrical signals. These signals are transmitted to the brain and formed into an image.

Photoreceptor: a specialized cell that detects light and converts it into an electrical signal. Photoreceptors are found within the retina.

Transcription Factor: a protein that is involved in regulating which genes are turned on and off within a cell.

Conflict of Interest Statement

The writer and editor have no conflicts to declare.

Citation of Article Reviewed

La Spada AR, Fu YH, Sopher BL, et al. Polyglutamine-Expanded Ataxin-7 Antagonizes CRX Function and Induces Cone-Rod Dystrophy in a Mouse Model of SCA7. Neuron, 2001 31:913–27. (https://www.ncbi.nlm.nih.gov/pubmed/11580893)