Designing a new “measuring stick” for ARSACS

Written by Dr. Brenda Toscano Márquez  Edited by Dr. Ray Truant

ARSACS researchers develop a better “measuring stick”, or disease severity index that can help better assess the progression of motor symptoms and compare different groups of ARSACS patients.

How does your doctor know you are sick? In short: measurements. Doctors record your weight, blood pressure, temperature, glucose levels, etc. The complex relationship between these biomarkers should indicate if you are healthy, or if not, to what degree you deviate from the healthy range.

Of course, each disease has a unique set of symptoms and characteristics. Performing the right measurements, with the right scales, is key to determining the type of disease, the course of treatment and most importantly, to know if the treatment is working. It would be careless and even dangerous if, for example, your doctor weighed you with a scale that could only detect a change of 10 kilograms. Even worse would be to focus on this measurement when you are actually suffering from high blood pressure.

yellow measuring tape wrapped up in ball
Photo by Marta Longas on

Patients with cerebellar ataxia also need physicians to perform the right measurements that take into account their particular type of ataxia. Proper measurements show how fast symptoms are progressing and if treatments and therapies are having an effect. Cynthia Gagnon and colleagues published a paper in the journal of Neurology this past year in which she and her collaborators designed a new set of measurements or “disease severity index” to track the symptoms better. The new index is designed for adult patients with a type of cerebellar ataxia called ARSACS. The researchers hope that this new index which they call DSI-ARSACS will help clinicians better assess how the disease is progressing, and will provide the means to compare different groups of patients.

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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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How an ataxia gene increases the risk for Alzheimer’s disease

Written by Dr. Judit M. Perez Ortiz Edited by Dr. Marija Cvetanovic

In a tour de force study, a collaborative team of scientists led by Dr. Rudolph Tanzi (Harvard Medical School) and Dr. Huda Zhogbi (Baylor College of Medicine) found a novel relationship between the Spinocerebellar ataxia type 1 gene (ATXN1) and Alzheimer’s disease.

Alzheimer’s disease is the most common neurodegenerative disease and the most common cause of dementia. Its precise etiology remains the subject of intense investigation and debate. Alzheimer’s is a devastating disease. Persons with Alzheimer’s disease experience difficulties thinking and remembering things. As the disease worsens other symptoms begin to appear, such as getting lost easily, not recognizing loved ones, problems with language, and behavioral and psychiatric issues. In the more advanced stages, patients are completely dependent on their caregivers.

artist's sketch of a human brain, designed to look like electrical circuits
Drawing of a human brain, courtesy of Wikimedia.

Despite extensive research, a specific unifying cause of Alzheimer’s disease has not yet been identified, likely due to its complexity. There are a handful of genes responsible for a rare form of early onset Alzheimer’s disease that affects younger patients. However, the great majority of cases start late in life and have no known underlying cause (termed sporadic). While the major risk to develop Alzheimer’s disease is advanced age, scientists believe that clues to sporadic Alzheimer’s can be found in our genes. In this pursuit, hundreds of “risk genes” have been associated with Alzheimer’s disease and Ataxin-1 (ATXN1) has recently emerged as one of such risk genes. Yet how ATXN1 influence Alzheimer’s disease was not understood.

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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

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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