Decreasing ATXN3 levels can alleviate some symptoms in an SCA3 mouse model

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?

white lab mouse being held by person wearing gloves
Image of a mouse in a laboratory environment. Photo by Pixabay on Pexels.com

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Connecting the dots between genetics and disease in SCA13

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.

two puzzle pieces being connected together by hands
Two puzzle pieces being connected together, much like how researchers connect pieces of data together to understand disease. Photo by Pixabay on Pexels.com

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.

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Stressed to the limit: Uncovering a role for oxidative stress in spinocerebellar ataxia type 7

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.

red pencil writing the word stress
Photo by Pedro Figueras on Pexels.com

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.

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RNA-binding Protein Found to Play a Role in SCA2 Neurodegeneration

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.

close of of chain with metal links
Image of a metal chain. If a “weak link” is found in the chain of events that go amiss in SCA2, scientists could focus on this area to research possible treatment.  Photo by Pixabay on Pexels.com

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Molecular Mechanism behind Purkinje Cell Toxicity in SCA1 Uncovered

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.

science laboratory
Image of scientific laboratory. Photo by Martin Lopez on Pexels.com

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The Discovery of SCA8

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.

mother with her two children looking at a mountain
Image of mother with her children. SCA8 was initially identified in a mother and daughter. SCA8 also shows maternal penetrance bias. Photo by Josh Willink on Pexels.com

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Welcome to SCAsource!

About six months ago, scientists from all over the world converged on the 2018 Ataxia Investigators Meeting. Colleagues and students discussed the latest advancements in ataxia research. Researchers were able to connect with patients and families, letting them know what progress was being made.

Some of the discussion between trainees at this meeting highlighted how great it was to be able to speak with patients and let them know what was happening in the lab. It was unfortunate that this opportunity only happened every two years.

It was at this meeting where the idea for SCAsource was born: a website where scientific articles on SCAs and related ataxias would be translated into plain language that anyone would be able to understand.

Road stretching out into the distance
The journey begins. Photo by Nextvoyage on Pexels.com

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Protein kinase C to the Rescue in Spinocerebellar Ataxias

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 how to increase their resistance to degeneration, are clear.

Three cartoon brains
Image courtesy of the The Internet Archive/Nielsen Malaysia

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Dynamic duo strikes again – Orr and Zoghbi discover the primary driver of SCA1 pathology in the cerebellum

Written by Logan Morrison Edited by Dr. Hayley McLoughlin

Research group uncovers the key molecular interaction that causes spinocerebellar ataxia type 1 (SCA1).

Blue and silver stethoscope
Photo by Pixabay on Pexels.com

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.

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Early Cerebellum Development Abnormality in Adult-Onset Spinocerebellar Ataxia Type 1

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.

Cartoon of a neuron
Artist representation of a neuron. Image courtesy of Pixabay

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.

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