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.
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.
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?
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.
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.
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.
Written by Carrie A. Sheeler Edited by Dr. Ronald A.M. Buijsen
RNAi reduces levels of disease-causing Ataxin-1 in SCA1 model mice, easing symptoms of disease when injected both before and after symptom onset.
Lowering the amount of the disease-causing mutant Ataxin-1 protein in affected cells and tissues improves symptoms of disease in spinocerebellar ataxia type 1 (SCA1) mouse models. Like patients with SCA1, mouse models exhibit worsening coordination and degeneration of neurons, beginning in adulthood. Previous work has used genetic manipulation before disease onset (Zu et al 2004). This prevents or delays the onset of disease in SCA1 mouse models. When this is done soon after the onset of symptoms, associated markers of disease are reversed. This suggests that there is a window of time after symptoms start wherein mutant Ataxin-1 can be targeted to improve patient outlook. The 2016 paper by Keiser and colleagues seeks to further study this effect, using RNA interference as a strategy to reduce disease-causing levels of Ataxin-1. As there is no current treatment for Ataxin-1, this is an important step towards assessing possible treatment strategies that could be useful in patients.
Current strategies seek to decrease the amount of Ataxin-1 made in cells by targeting messenger RNA (mRNA)- the blueprints for proteins in a cell- for destruction. RNA interference (RNAi) is one such method which harnesses normal cellular processes to degrade specific mRNAs. In Keiser’s 2016 paper, a modified virus carrying a short sequence of DNA is injected into the brain of a mouse with SCA1. When this virus is injected, the DNA sequence enters the cells of nearby brain regions and stops the production of specific mRNA. In this case, it is Ataxin-1 mRNA that is specifically targeted. As Ataxin-1 mRNA are destroyed, the amount of Ataxin-1 protein made in the cell decreases.
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.