Written by Dr. Terri M Driessen Edited by Dr. W.M.C. van Roon-Mom
Antisense oligonucleotides: a potential treatment for SCA3 that partially rescues SCA3 disease mouse models
Identifying new ways to slow down or delay neurodegenerative diseases has been a key research focus in the SCA field. There are many avenues that scientists can take to address this question. One method is to target the disease-causing protein: by lowering the levels of the disease-causing protein, scientists may be able to alter disease progression. These methods have recently been used in studies in other neurodegenerative disorders, like SCA2, Amyotrophic Lateral Sclerosis (ALS), and Huntington’s disease.
Prior work by the laboratory of Hank Paulson at the University of Michigan has suggested these methods may also work in SCA3. They used antisense oligonucleotides (ASOs) to lower the SCA3 disease-causing protein. ASOs are short DNA sequences that bind to specific pieces of RNA. When the ASOs bind to RNA, it is broken down and no protein is made. The Paulson laboratory designed ASOs that bind to ATXN3, which is the RNA associated with SCA3. These ASOs were able to lower the expression of mutant ATXN3 (Moore, et al. 2017). Importantly, they were capable of lowering the expression of mutant ATXN3 in both mouse models of SCA3 and SCA3 patient fibroblasts (Moore, et al. 2017). By removing the SCA3-causing protein from cells, they predicted that the cells would have a better chance at surviving.
This previous work was promising, but several questions remained. How long would one ASO treatment work? Would the ASO work even after the SCA3 mice started showing symptoms? Are there any obvious side effects, like increased inflammation, after ASO injection? And importantly, would lowering ATXN3 levels help with motor coordination problems in SCA3 mice?
Written by Dr. David D. Bushart Edited by Dr. Carolyn J. Adamski
How one research group worked to identify previously unknown causes of SCA13, and what we can learn from their strategy.
With so many different causes of cerebellar ataxia, how are doctors able to make an accurate diagnosis? This is an extremely important question for doctors, research communities, and patients. For doctors, knowing the underlying genetic cause for a case of ataxia is critical not only for formulating a more specific treatment plan, but also for performing informed genetic screens to determine if a patient’s family members are at risk for developing ataxia. For researchers, knowing what causes a certain type of ataxia allows for the development of new treatment strategies. And for patients, an accurate diagnosis can, importantly, provide peace-of-mind.
Unfortunately, getting to this point of diagnosis can still be a difficult task in a lot of cases – up to 20 percent of ataxia cases do not have a confirmed genetic cause (Hadjivassiliou et al., Journal of Neurology, Neurosurgery, and Psychiatry 2016). This is clearly an area for improvement in the field of ataxia research. Fortunately, many research groups are making efforts to improve our knowledge of the many different causes for cerebellar ataxia, how frequently they appear, and how we might be able to better treat them.
Though there are many studies that are continuously being performed and are constantly improving our knowledge of the specific causes of cerebellar ataxia, this summary will focus on the work of one group (Figueroa et al., PLoS One 2011). The research team, led by Dr. Stefan Pulst at the University of Utah, sought to better identify the frequency of different genetic mutations causing SCA13, a rare, dominantly-inherited form of spinocerebellar ataxia caused by mutations in a gene called KCNC3.
Written by Siddharth Nath Edited by Dr. Ray Truant
Oxidative stress is a hot topic in neurodegenerative disease research. New findings from Dr. Jonathan Magaña’s lab in Mexico show increases in measures of damage from oxygen compounds in SCA7 patients versus healthy individuals. This suggests that this type of chemical stress may be a critical step in triggering the death of brain cells in SCA7.
You’re stressed – whether you like it or not
You may not realize it, but all of the cells in your body are, at some point or another, undergoing stress. Now, this isn’t the same as what we normally take the word “stress” to mean. Your cells aren’t cramming for an exam, nor are they worried about an upcoming job interview. Instead, stress at the cellular level refers to the challenges cells face in the form of environmental extremes (like temperature changes), mechanical damage, exposure to toxins, and dysregulation of stress responses.
A particularly nasty type of stress that cells must contend with is oxidative stress. This results from an imbalance in the levels of reactive oxygen species (hence the term ‘oxidative’) within a cell and the cell’s ability to clear away these species. Reactive oxygen species form inside of cells as a byproduct of normal metabolism, and every cell has mechanisms to help with their clearance. These mechanisms, however, can become impaired. This could end up being disastrous because, when not removed properly, reactive oxygen species can wreak havoc in the cell: they have the ability to directly damage every cellular component, including proteins, lipids, and DNA.
Interestingly, oxidative stress increases naturally as we age and is a normal part of growing older. Oxidative stress is a topic of intense study and has been implicated in everything from cancer and bone disease to other neurodegenerative disorders (such as Alzheimer’s disease and Huntington’s disease). An inability to cope with or respond to increases in oxidative stress associated with aging may explain why many neurodegenerative disorders occur later in life, despite the fact that affected individuals express the disease gene from birth.
Written by Dr. Hayley McLoughlin Edited by Dr. Gülin Öz
Is Staufen1 a kink in the SCA2 toxicity chain that can be exploited?
When a cell is stressed, it can initiate a mechanism to protect messenger RNAs (mRNAs) from harmful conditions. It does this by segregating the mRNAs, then packaging them up in droplets known as RNA stress granules. ATXN2, the protein that is mutated in SCA2, has previously been reported as a key component in the formation of these RNA stress granules (Nonhoff et al., 2007). This observation has led researchers to take a closer look at stress granule components, especially in the context of SCA2 disease tissues.
Written by Dr. Chandrakanth Edamakanti Edited by Dr. Hayley McLoughlin
Recent study decodes the protein signature of toxic Purkinje cells, finding that Purkinje cell mTORC1 signaling is impaired in SCA1.
Spinocerebellar ataxia type 1 (SCA1) is a late onset cerebellar neurodegenerative disorder caused by a mutation (in this case, an abnormal polyglutamine stretch) in the Ataxin-1 gene. People with this condition experience problems with coordination and balance, a set of symptoms known as ataxia. The protein produced by this faulty gene, ATXN1, is particularly toxic to the Purkinje cells, the sole output neurons of the cerebellum. However, the reason behind the selective toxicity of Purkinje cells in SCA1 is unknown.
The main focus of this article is to address this question. It is the first study to find the protein signature of toxic Purkinje cells in SCA1 mice. In the end, the authors identified widespread protein changes that are associated with Purkinje cell toxicity.
Written by Logan Morrison Edited by Dr. Sriram Jayabal
Stanford researchers accidentally discover a new role (reward prediction) for the cerebellum, the primary brain region affected by spinocerebellar ataxias.
Would you believe that the part of your brain that enables you to perform simple, everyday tasks (like jogging or walking) also controls your ability to do more complex tasks (like throwing a curve ball) with accuracy? It’s true! Every one of our body’s movements is adjusted by a brain region known as the cerebellum – a primary area of pathology in spinocerebellar ataxias. The name “cerebellum” is a combination of the Latin word for the brain – cerebrum – and the Latin suffix -ellus, which means small. While this “little brain” might not take up much room, it actually contains the vast majority of the nerve cells (known as neurons) in the central nervous system1. Take a look at the image included with this article to see for yourself: even without the red highlighting, the cerebellum should be instantly recognizable as the distinctive structure in the bottom right, so folded and densely-packed that it looks a bit like something you’d find on the branches of a fern or shrub. Among these many folds are the circuits that fine-tune our motor output, providing us with the ability to move our bodies with ease and precision.
For decades, not much else was said about the function of the cerebellum beyond its primary role in tweaking movement. Recently, though, there have been some hints that there is more to this part of the brain than we might have thought: brain imaging studies of patients suffering from bipolar disorder, for instance, have sometimes shown abnormalities in the cerebellum3, 4. Cerebellar abnormalities have been implicated in a variety of other diseases, as well, including autism spectrum disorders, schizophrenia, Alzheimer’s disease, and multiple sclerosis5, 6. Now, thanks to the hard work of scientists at Stanford University7 – as well as a bit of luck – we know that the cerebellum is not only involved in how we move, but why.
Written by Dr. Hannah K Shorrock Edited by Dr. Judit M Perez Ortiz
How one team uncovered the first SCA known to be caused by a CTG repeat expansion mutation
Identifying the gene that causes a type of ataxia not only gives patients and their families a clearer diagnosis and prognosis, but also allows scientists to model the disease. Through genetic animal models of ataxia, researchers can study how a single mutation causes a disease and how we can try to slow, halt, or even reverse this process. It is this path through research that may eventually lead from gene discovery to the development of effective therapies.
The gene that causes spinocerebellar ataxia type 8 (SCA8) was first described in a research article published in 1999. Since then, many research articles on SCA8 have been published, including research into the DNA repeat expansions that cause the ataxia, the cellular processes that lead to ataxia, and the development of multiple animal models of SCA8. Together, these move the scientific community further along the road of research.
Written By Dr. Marija Cvetanovic Edited by Dr. Sriram Jayabal
Protein kinase C: one protein that may help to protect against cerebellar neuronal dysfunction & death in spinocerebellar ataxias
Among the estimated 86 billion brain cells (known as “neurons”) in the human body (Azevedo et al., 2009), there is a small population of cells called Purkinje neurons. Though they only constitute a modest ~14-16 million cells, (Nairn et al., 1989), death or dysfunction in Purkinje neurons can cause you to lose your ability to walk coherently – a clinical symptom known as “ataxia.” This is because Purkinje neurons are the major work horse of the cerebellum, which is the part of the brain that fine-tunes our movement. While different types of hereditary spinocerebellar ataxias (SCAs) are caused by mutations in different genes, they all exhibit one thing in common: Purkinje neurons undergo severe degeneration. Neither the reasons for this selective vulnerability of Purkinje neurons in ataxia, nor howto increase their resistance to degeneration, are clear.
Written by Logan Morrison Edited by Dr. Hayley McLoughlin
Research group uncovers the key molecular interaction that causes spinocerebellar ataxia type 1 (SCA1).
When we talk and think about human disease, it is natural to focus on causes. For some disorders, the source of the problem is clear: there’s no question why a patient with a spinal cord injury has paralysis, for instance. Other diseases, like schizophrenia, are incredibly difficult to attribute to specific environmental influences or genetic mutations (probably because they are the result of a variety of subtle factors that add up to cause the disorder).
Our current understanding of spinocerebellar ataxia type 1 (SCA1) falls somewhere in between these extremes. For years, we have known that SCA1 is caused by a polyglutamine expansion in the ataxin-1 gene. In short, this means that SCA1 patients have experienced a rare copying error in their genetic code in the region that is responsible for guiding the production of the Ataxin-1 protein (ATXN1). However, there are still quite a few questions surrounding what ATXN1 does under normal circumstances. This has meant that, so far, scientists have not been able to show why a polyglutamine expansion in the ataxin-1 gene causes the cells of the cerebellum, spine, and brainstem to lose their normal function in cases of SCA1.
Written by Dr. Vitaliy V Bondar Edited by Dr. Chandrakanth Edamakanti
Researchers for the first time identified that spinocerebellar ataxia type 1 (SCA1) may have roots in early cerebellar circuit malfunction.
Since the discovery of the cause of SCA1, researchers have wondered: why does it take three to four decades of life for symptoms to reveal themselves? This late stage disease progression is surprising, given that early molecular changes are observed in many SCA1 animal models. Furthermore, this is true for many other neurodegenerative diseases (i.e., that molecular changes precede symptoms). Studying and understanding this delay in symptom onset may reveal potential treatment options to mitigate and slow down the progression of the disease.
The cerebellum is one of the most important brain regions for SCA1 research because it is responsible for the fine movement control that SCA1 patients have difficulty with. Moreover, the cerebellum is the brain region that degenerates the earliest in SCA1. Given that SCA1 symptoms strike late in adulthood, many scientists thought that there would not be any cellular changes during the cerebellum’s development (that is, early in SCA1 patients’ lives). However, Chandrakanth Edamakanti, a postdoctoral scientist in Puneet Opal’s laboratory at Northwestern University, has recently demonstrated that the stem cells in the cerebellum behave differently in SCA1. These stem cells, which exist in the cerebellum for the first three weeks after birth, help to complete cerebellar development by adding new neurons and supporting cells (known as glia). Dr. Edamakanti and colleagues have shown that, in SCA1, this process is disturbed, which likely contributes to Purkinje cell toxicity at later ages. This represents the first cellular and anatomical difference that has been seen in neurons prior to degeneration in SCA1. Other neurodegenerative diseases, including Alzheimer’s, Huntington’s and Parkinson’s, may also stem from such developmental defects that set the stage for later disease vulnerability.