A novel gene therapy-based approach with therapeutic potential in SCA3

Written by Dr. Ramya Lakshminarayan Edited by Dr. Judit M. Perez Ortiz

Cholesterol to the rescue: An alternative approach to treating SCA type 3 using gene therapy.

Spinocerebellar ataxia type 3 (SCA3) is a movement disorder that is caused by genetic mutations in a protein named Ataxin-3. Neurons in the cerebellum, striatum, and substantia nigra are important for movement, and these are affected in SCA3.

The mutant form of Ataxin-3 builds up in these neurons, eventually causing neurodegeneration and neuronal loss. The abnormal accumulation of mutant Ataxin-3 is in part due to impaired protein clearance, which is a hallmark of many other neurodegenerative diseases. Degradation (breaking down) and clearance (getting rid of) of protein aggregates are therefore crucial in the pathophysiology of neurodegeneration.

The balance between protein synthesis (creation) and degradation (destruction) is critical to the health of neurons. One of the ways in which neurons degrade proteins is called autophagy. This process is mediated by organelles called lysosomes in cells. Lysosomes employ digestive proteins to break down complex protein aggregates into simpler forms, which are eventually recycled. Hence, the transport of proteins to lysosomes is an important step in protein degradation. In a recent study, Clevio and colleagues explore the role of cholesterol in mediating protein degradation and ensuring neuroprotection in SCA3.

laboratory scientisy using a pipette to transfer liquid between tubes
Photo of a researcher preparing samples, courtesy of Pixabay.

Cholesterol is a well-known biological molecule that is essential to cells for regulating various processes. However, abnormally elevated levels of cholesterol are associated with heart disease, and its production is the target of pharmacological therapies. As with proteins, homeostatic fine-tuning of cholesterol levels is maintained by a balance of production and degradation.  In many neurodegenerative disorders, such as Alzheimer’s disease and Huntington’s disease, cholesterol metabolism and turnover is impaired.  The cholesterol biosynthetic pathway facilitates production and its metabolism is mediated by an enzyme called cholesterol 24-hydroxylase (CYP46A1). CYP46A1 converts cholesterol to 24-hydroxycholesterol, a form capable of crossing the blood-brain barrier. This conversion allows the efflux of cholesterol from neurons. CYP46A1 is, therefore, necessary for cholesterol efflux and the efflux of cholesterol activates the cholesterol biosynthetic pathway. The cholesterol biosynthetic pathway produces many precursors important for protein transport and autophagy.

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Snapshot: How does CAG tract length affect ataxia symptom onset?

The instructions our bodies need to grow and function are contained in our genes. These instructions are made up of tiny structures called nucleobases. There are four types of nucleobases in DNA: adenine (A), cytosine (C), guanine (G), thymine (T). By putting these four nucleobases in different orders and patterns, this writes the instructions for our body.

artists drawing of a blue DNA molecule
A cartoon strand of DNA. Image by PublicDomainPictures from Pixabay

Some of the genes contain long sections of repeating ‘CAG” instructions, called CAG tracts. Everyone has repeating CAG tracts in these genes, but once they are over a certain length they can lead to disease. Some ataxias are caused by this type of mutation, including SCA1, SCA2, SCA3, SCA6, SCA7 and SCA17. These are often called polyglutamine expansion disorders. This is because “CAG” gives the body instructions to make the amino acid glutamine. You can read more about what is polyglutamine expansion in our past Snapshot about that subject.

For each disorder caused by a CAG expansion mutation, the number of times the CAG is repeated in a particular gene will determine whether someone will develop the disease. Repeat lengths under this number will not cause symptoms and repeat lengths over the threshold will usually lead to ataxia. When someone undergoes genetic testing for ataxia, doctors will be able to tell them the length of these CAG tracts and whether they have a CAG repeat number in one of these genes that is over the threshold. This table gives a summary of different CAG expansion mutations that can lead to ataxia and how the length of the repeat affects age of onset.

Affected Gene Normal
Repeat Size
Repeat Size
SCA6CACNA1A 4-1821-33
SCA17 TBP25-4246-63

For SCA1, SCA2, SCA3, SCA6, and SCA7; longer CAG tracts are associated with earlier onset.

For SCA12, it is hard to predict the age of onset based on repeat length as SCA12 is so rare. Some individuals with long repeats don’t develop ataxia. One study found that longer CAG tract lengths are associated with earlier onset but that it does not affect the severity of symptoms.

For SCA17, Longer CAG tracts have separately been associated with an earlier age of onset and more severe cerebellar atrophy.

In general, people with longer repeat lengths in ataxia genes are likely to present with ataxia symptoms earlier in life. However, it is important to remember that there are many other factors involved. Other genes may have mutations that either worsen the progression of ataxia or protect against more severe symptoms. Therefore, in individual people, the length of the repeat is not always enough information to determine when that person will start showing symptoms, or how severe these symptoms will be.

If you would like more information about the genetic causes of SCAs, including information about genetic testing and what CAG repeat length might mean, take a look at these resources by the National Ataxia Foundation.

Snapshot written by Anna Cook and edited by Larissa Nitschke.

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Two or more birds with one stone: Designing a single therapeutic strategy to treat multiple types of spinocerebellar ataxia

Written by Dr. David Bushart Edited by Dr. Hayley McLoughlin

A newly-proposed treatment strategy might be effective against several forms of spinocerebellar ataxia and other CAG repeat-associated disorders

Upon receiving an initial diagnosis of spinocerebellar ataxia (SCA), a swarm of questions might enter a patient’s mind. Many of these questions will likely revolve around how to manage and treat their disease. What treatments are currently available to treat SCA? What can I do to reduce symptoms? Does SCA have a cure, and if not, are researchers close to finding one? Patients and family members who read SCASource may be able to answer some of these questions. Although scientists are aware of some of the underlying genetic causes of SCA, and patients can benefit greatly from exercise and physical therapy, there are unfortunately no current drug therapies that can effectively treat these diseases. However, this is a very exciting time in SCA research, since researchers are hard at work developing new treatment strategies for several of the most common SCAs. Many of these newly proposed therapies are specialized to treat a specific genetic subtype of SCA (e.g. SCA1, SCA3, etc.), which would allow these therapies to be very specific. However, these specialized efforts beg another question: would it be possible to treat different types of SCA with the same therapeutic strategy?

sketch of a human brain and spinal cord across a blue background
Artist’s sketch of a human brain. Image courtesy of Pixabay.

This is precisely what researchers wished to determine in a recent study, authored by Eleni Kourkouta and colleagues. This group of researchers used a technology called antisense oligonucleotides (often abbreviated ASO, or AON), to ask whether a single ASO could be used to treat multiple neurological disorders that have different underlying causes. Currently, most ASO technology depends on our ability to selectively target specific disease-causing genes, which allows the ASO to only recognize and act on the specific gene that is causing ataxia. Once recognized, these ASOs can recruit cellular machinery that lowers RNA levels of the disease-causing gene, thereby greatly limiting the amount of disease-causing protein that is produced (learn more in our What is RNA? Snapshot). This strategy has the potential to be very effective for treating SCAs that are associated with polyglutamine (polyQ) expansion (learn more in our What is Gene Therapy? Snapshot).

However, the type of ASO technology described above is not the only way to reduce levels of the disease-causing proteins in SCA. In this paper, Kourkouta and colleagues use a different type of ASO with a different mechanism of action, which also lowers levels of the disease-causing protein in two different SCAs.

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Eyes: Windows to peek at brain function in spinocerebellar ataxias

Written by Dr. Sriram Jayabal Edited by Dr. David Bushart

Eye movement deficits occur ubiquitously in spinocerebellar ataxias, even at early disease states, highlighting their clinical importance.

Imagine the different motor movements that you make in your everyday life. Many people think of actions that we perform using our hands and legs, such as reaching for objects or walking. Let’s zoom in on a different task: catching a baseball. You need to know where the ball is going to land so you can run to that spot, then guide your arms while diving, if need be, to catch the ball. For this to work perfectly, you need to see and follow the ball. Your eyes enable you to track the ball while it is moving. How can your eyes keep the ball in focus while you are running at full speed towards the spot where you expect the ball to land? Your eyes are equipped with muscles which enable the eyes to move so as to keep the visual scene in focus. These eye movements, as demanded by the needs of the current scenario, in this case, catching a baseball, are indispensable for us to see the world without any hindrance.

Woman with hand in a "C" shape in front of her face. She's focusing in on her eye.
The eyes may provide a window into spinocerebellar ataxia, even before other symptoms show up. Photo by fotografierende on Pexels.com

Which brain region gives us the power to do this?

The cerebellum, or “little brain”, which enables one to move their arms and legs precisely, also controls the way we move our eyes. Therefore, it is logical to posit that when cerebellum goes awry, it may lead to eye movement abnormalities. Several previous studies have shown this to be true in many spinocerebellar ataxias (SCAs), where non-gait symptoms such as eye movement abnormalities have been found to accompany gait deficits in advanced stages of the disease. However, recent work from pioneers in clinical ataxia research at the Harvard Medical School have shown that eye movement abnormalities are also commonly present in SCAs even in pre-symptomatic states. This study emphasizes the critical need to better document the history of eye movement deficits and track them throughout the progression of the disease. This will help researchers to develop better rating scales for ataxia.

In this study, a population of SCA patients (134 individuals) who exhibited different types of SCA (including SCA1, SCA2, SCA3, SCA5, SCA6, SCA7, SCA8 and SCA17) were assessed for eye movement abnormalities at different stages of the disease, from pre-symptomatic (with no gait deficits) to advanced stages (those who use a wheel-chair). First, it was found that ~78% of all pre-symptomatic individuals exhibited eye movement deficits, and these deficits became even more common as the disease progressed, where every single person in advanced stages exhibited eye movement deficits. Second, when researchers examined the eye movements closely, they found that different types of ataxia might cause different kinds of eye movement deficits. However, these results are only suggestive because of the small population size of early-stage SCA individuals in this study, and the types of assessments used. Therefore, future studies will require a larger population size and a thorough quantitative analysis of specific types of eye movement deficits to help characterize eye movement abnormalities in SCAs. Finally, the Brief Ataxia Rating Scale (BARS), a recently designed simple clinical test for ataxia, was further improved in this study to account for the clinically observed eye movement deficits in SCAs. With such a nuanced metric, an improved BARS score was found to correlate with the stage, severity and duration of the disease irrespective of the type of ataxia.

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Huntingtin: a new player in the DNA repair arsenal

Written by Dr. Ambika Tewari Edited by Dr. Mónica Bañez-Coronel

Mutations in the Huntingtin protein impair DNA repair causing significant DNA damage and altered gene expression

Our genome houses the entirety of our genetic material which contains the instructions for making the proteins that are essential for all processes in the body. Each cell within our body, from skin cells that provide a crucial protective barrier, immune cells that protect us from invading species and brain cells that allow us to perceive and communicate with the world contains genetic material. During early development in every mammalian species, there is a massive proliferation of cells that allows the development from a one-cell stage embryo to a functional body containing trillions of cells. For this process to occur efficiently and reliably, the instructions contained in our genetic material need to be precisely transmitted during cell division and its integrity maintained during the cell’s life-span to guarantee its proper functioning.

There are many obstacles that hamper the intricate and highly orchestrated sequence of events during development and aging, causing alterations that can lead to cell dysfunction and disease. Internal and external sources of DNA damage constantly bombard the genome. Examples of external sources include ultraviolet radiation and exposure to chemical agents, while internal sources include cell processes that can arise, for example, from the reactive byproducts of metabolism. Fortunately, nature has evolved a special group of proteins known as DNA damage and repair proteins that act as surveyors to detect erroneous messages. These specialized proteins ensure that damage to the DNA molecules that encode our genetic information is not passed to the new generation of cells during cell division or during the expression of our genes, ultimately protecting our genome. Many genetic disorders are caused by mutations in the genetic material. This leads to a dysfunctional RNA or protein with little or no function (loss of function) or an RNA or protein with an entirely new function (gain of function). Since DNA repair proteins play a crucial role in identifying and targeting mistakes made in the message, it stands to reason that impairment in the DNA repair process might lead to disease. In this study, Rui Gao and colleagues through an extensive collaboration sought to understand the connection between altered DNA repair and Huntington’s disease.

Blue strands of DNA
An artist’s rendering of DNA molecules.

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