Regulating ataxin-1 expression as a therapeutic avenue for SCA1

Written by Dr. Hannah Shorrock   Edited by Dr. Hayley McLoughlin

Nitschke and colleagues identify a microRNA that regulates ataxin-1 levels and rescues motor deficits in a mouse model of SCA1

What if you could use systems already in place in the cell to regulate levels of toxic proteins in disease? This is the approach that Nitschke and colleagues took to identify the cellular pathways that regulate ataxin-1 levels. Through this strategy, the group found a microRNA, a small single-stranded RNA, called miR760, that regulates levels of ataxin-1 by directly binding to its mRNA and inhibiting expression. By increasing levels of miR760 in a mouse model of SCA1, ataxin-1 protein levels decreased and motor function improved. This approach has the potential to identify possible therapies for SCA1. It may also help identify disease-causing mutations in ataxia patients with unknown genetic causes.

Spinocerebellar Ataxia type 1 (SCA1) is an autosomal dominant disease characterized by a loss of coordination and balance. SCA1 is caused by a CAG repeat expansion in the ATXN1 gene. This results in the ataxin-1 protein containing an expanded polyglutamine tract. With the expanded polyglutamine tract, ataxin-1 is toxic to cells in the brain and leads to dysfunction and death of neurons in the cerebellum and brainstem.

As with all protein-coding genes, surrounding the protein coding region of ATXN1 gene are the 5’ (before the coding sequence) and 3’ (after the coding sequence) untranslated regions (UTRs). These regions are not translated into the final ataxin-1 protein product but are important for the regulation of this process. Important regulation factors called enhancers and repressors of translation located in 5’ and 3’ UTRs. ATXN1 has a long 5’ UTR. Genes that require fine regulation, such as growth factors, are often found to have long 5’ UTRs: the longer a 5’ UTR, the more opportunity for regulation of gene expression. The group, therefore, tested the hypothesis that the 5’ UTR is involved in regulating the expression of ataxin-1.

In their initial studies, Nitschke and colleagues identified that the ATXN1 5’UTR is capable of reducing both protein and RNA levels when placed in front of (5’ to) a reporter coding sequence. One common mechanism through which this regulation of gene expression could be occurring is the binding of microRNAs, or miRNAs, to the ATXN1 5’UTR. miRNAs are short single-stranded RNAs that form base pairs with a specific sequence to which the miRNA has a complementary sequence; this leads to regulation of expression of the mRNA to which the miRNA is bound.

3d illustration of single-strand ribonucleic acid
Artist drawing of single-stranded RNA. Photo used under license by nobeastsofierce/Shutterstock.com.

Using an online microRNA target prediction database called miRDB, the group identified two microRNAs that could be responsible for these changes in gene expression through binding to the ATXN1 5’ UTR. By increasing the expression of one of these microRNAs, called miR760, ataxin-1 protein levels were reduced in cell culture. Conversely, using a miR760 inhibitor so that the miRNA could not perform its normal functions led to increased levels of ataxin-1. Together this shows that miR760 negatively regulates ataxin-1 expression.

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Identifying FDA-approved molecules to treat SCA6

Written by Dr Hannah Shorrock Edited by Dr. Larissa Nitschke

Pastor and colleagues identify FDA-approved small molecules that selectively reduce the toxic polyglutamine-expanded protein in SCA6.

Selectively targeting disease-causing genes without disrupting cellular functions is essential for successful therapy development. In spinocerebellar ataxia type 6 (SCA6), achieving this selectivity is particularly complicated as the disease-causing gene produces two proteins that contain an expanded polyglutamine tract. In this study, Pastor and colleagues identified several Food and Drug Administration (FDA) approved small molecules that selectively reduce the levels of one of these polyglutamine-containing proteins without affecting the levels of the other protein, which is essential for normal brain function. By using drugs already approved by the United States Food and Drug Administration to treat other diseases, referred to as FDA-approved drugs, the team hopes to reduce the time frame for pre-clinical therapy development.

SCA6 is an autosomal dominant ataxia that causes progressive impairment of movement and coordination. This is due to the dysfunction and death of brain cells, including Purkinje neurons in the cerebellum. SCA6 is caused by a CAG repeat expansion in the CACNA1A gene. CACNA1A encodes two proteins: the a1A subunit, the main pore-forming subunit of the P/Q type voltage-gated calcium ion channel, as well as a transcription factor named a1ACT.

The a1A subunit is essential for life. Its function is less affected by the presence of the expanded polyglutamine tract than that of a1ACT. The transcription factor, a1ACT, controls the expression of various genes involved in the development of Purkinje cells. Expressing a1ACT protein containing an expanded polyglutamine tract in mice causes cerebellar atrophy and ataxia. While reducing levels of the a1A subunit may have little effect on SCA6 disease but impact normal brain cell function, reducing levels of a1ACT may improve disease in SCA6. Therefore, Pastor and colleagues decided to test the hypothesis that selectively reducing levels of the a1ACT protein without affecting levels of the a1A protein may be a viable therapeutic approach for SCA6.

Colorful pile of medicines in blister packs which color are White, Yellow, Black and Pink pills.
By using drugs already approved by the FDA, the team hopes to reduce the time frame for pre-clinical therapy development. Photo used under license by Wanchana Phuangwan/Shutterstock.com.
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Levels of Capicua may make SCA1 neurodegeneration worse in parts of the brain

Written by Stephanie Coffin Edited by Dr. Brenda Toscano

Ataxin-1 may not be the only protein important in driving neurodegeneration in SCA1

Why does a protein that cause disease only cause toxicity in specific regions of the brain, despite being in all cells of the body?  This is the question authors attempt to answer in this article, with a focus on spinocerebellar ataxia type 1 (SCA1) and the disease causing protein, Ataxin-1.  SCA1 is a polyglutamine expansion disorder, meaning patients with the disease have a CAG repeat in the ATXN1 gene that is larger than that of the healthy population.  This mutant allele is then translated into a mutant protein, causing SCA1.  Ataxin-1 protein is expressed throughout the entire brain, however, toxicity (cell death and problems) is mainly restricted to neurons of the cerebellum and brainstem.  This phenomenon is called “selective vulnerability” and refers to disorders in which a restricted group of neurons degenerate, despite widespread expression of the disease protein.  Selective vulnerability occurs in many diseases, including Alzheimer’s, Huntington’s, and Parkinson’s disease and is currently under investigation by many scientists in the field of neurodegeneration.

In SCA1, this selective vulnerability can be narrowed further in the cerebellum. The cerebellum is broken down into lobules (I-X), with lobules II-V described as the anterior region and lobules IX-X as the nodular zone. Studies have previously shown cerebellar Purkinje cells to be particularly sensitive to mutant ataxin-1, and within the cerebellum, neurons in the anterior region degenerate faster than those in the nodular zone.  This paper wanted to understand the mechanism of this interesting biology, hypothesizing that there are genes whose are expressed mainly in these zones could correlate with the pattern of Purkinje cell degeneration. To this end, the authors used the mouse model ataxin-1 [82Q], which overexpresses human ataxin-1 with 82 CAG repeats specifically in cerebellar Purkinje cells.

Doctor howing up a scan of the human brain
Why do some parts of the brain degenerate in SCA1, when the disease causing protein is expressed in all pWhy do some regions of the brain degenerate in SCA1, when the disease-causing protein is expressed in all parts of the body? Why don’t other regions show the same signs of disease? This is what researchers sought to find out in this study. Photo by Anna Shvets on Pexels.com

First, the authors confirmed the finding that neurons from the anterior region of the cerebellum degenerate earlier than those in the nodular zone.  They did this by assessing the health and number of Purkinje cells, which indeed appeared to be better in the cells located in the nodular zone.  Next, techniques assessing expression of RNA in SCA1 and control cerebellum, showed that there are a number of genes which are uniquely dysregulated in the anterior cerebellum of SCA1 mice.  Neurons function and communicate with each other via ion channels, and interestingly, the genes found to be dysregulated in the anterior cerebellum of SCA1 mice were related to ion channel signaling.

Continue reading “Levels of Capicua may make SCA1 neurodegeneration worse in parts of the brain”

Spotlight: The Neuro-D lab Leiden

Principal Investigator: Dr. Willeke van Roon-Mom

Location: Leiden University Medical Centre, Leiden, The Netherlands

Year Founded: 1995

What disease areas do you research?

What models and techniques do you use?

A group photo of members of the Neuro-D lab Leiden standing outside on a patio.
This is a group picture taken during our brainstorm day last June. From left to right: Boyd Kenkhuis, Elena Daoutsali, Tom Metz, Ronald Buijsen, Willeke van Roon-Mom (PI), David Parfitt, Hannah Bakels, Barry Pepers, Linda van der Graaf and Elsa Kuijper. Image courtesy of Ronald Buijsen.

Research Focus

What is your research about?

The Neuro-D research group studies how diseases develop and progress at the molecular level in several neurodegenerative diseases. They focus on diseases that have protein aggregation, where the disease proteins clump up into bundles in the brain and don’t work correctly.

We focus strongly on translational research, meaning we try to bridge the gap between research happening in the laboratory to what is happening in medical clinics. To do this we use more “traditional” research models like animal and cell models. But we also use donated patient tissues and induced pluripotent stem cell (iPSC) models, which is closer to what is seen in medical clinics.

Our aim is to unravel what is going wrong in these diseases, then discover and test potential novel drug targets and therapies.

One thing we are doing to work towards this goal is identifying biomarkers to measure how diseases progress over time. To do this, we use sequencing technology and other techniques to look at new and past data from patients.

Why do you do this research?

So far there are no therapies to stop the progression of ataxia. If we can understand what is happening in diseases in individual cells, we can develop therapies that can halt or maybe even reverse disease progression.

Identifying biomarkers is also important, because it will help us figure out the best time to treat patients when we eventually have a therapy to test.

Stylized logo for the Dutch Center for RNA Therapeutics
The Neuro-D lab Leiden is part of the Dutch Center for RNA Therapeutics, which focuses on RNA therapies like antisense oligonucleotides. Logo designed by Justus Kuijer (VormMorgen), as 29 year old patient with Duchenne muscular dystrophy.

Are you recruiting human participants for research?

Yes, we are! We are looking for participants for a SCA1 natural history study and biomarker study. More information can be found here. Please note that information about this study is only available in Dutch.

Fun Fact

All our fridges and freezers have funny names like walrus, seal, snow grouse and snowflake.

For More Information, check out the Neuro-D lab Leiden website!


Written by Dr. Ronald Buijsen, Edited by Celeste Suart

Spotlight: The Watt Lab

Watt lab logo of a neuron

Principal Investigator: Dr. Alanna Watt

Location: McGill University, Montreal, Canada

Year Founded: 2011

What disease areas do you research?

What models and techniques do you use?

Research Focus

What is your research about?

We are interested in how the cerebellum influences motor coordination in both the healthy brain and in models of disease and aging. By identifying changes in the cerebellum underlying ataxias and aging, we hope to discover new treatments for patients.

Why do you do this research?

We want to understand how the cerebellum works and use this knowledge to understand the changes in the cerebellum that lead to ataxia. As a lab, we are particularly interested in studying rare disorders like SCA6 and ARSACS.

These disorders have limited treatment options. We hope that by understanding how the cerebellum works differently in these disorders, we will be able to identify new treatments to help ataxia patients.

We are also interested in identifying common changes between different types of ataxia, to find out whether treatments identified in one form of ataxia might also help other ataxia patients.

Six slippers with a variety of designs, includes brain cells and mice

Fun Lab Fact

We got together and made our own slippers to keep cozy in our office. If you look at the picture closely you might be able to spot some cells from the cerebellum on some of them!

Image courtesy of Anna Cook.

For More Information, check out the Watt Lab Website!


Written by The Watt Lab, Edited by Celeste Suart