ASOs clear toxic protein from cells, reducing ataxia in SCA2 mice

Written by Anna Cook and Dr. Alanna Watt Edited by Dr. Vitaliy V. Bondar

Scientists uncover a promising therapeutic avenue to treat spinocerebellar ataxia type 2 (SCA2).

Spinocerebellar ataxia type 2 (SCA2) is a progressive ataxia caused by a mutation in the ATXN2 gene. This mutation causes a tract of the amino acid glutamine in the ataxin 2 protein to expand, making it toxic to cells. This type of mutation – known as a polyglutamine expansion – is common to several neurodegenerative diseases, including Huntington’s Disease and several forms of ataxia. One treatment strategy that has been devised for polyglutamine diseases such as SCA2 is to remove the toxic protein from cells. And, in their tour de force SCA2 paper from 20171, this is precisely what Scoles and colleagues attempted to do. Removing protein levels is a particularly promising strategy for SCA2, since previous research from the authors of this paper has shown that a complete loss of healthy ataxin 2 protein in cells does not cause any major detectable behavioural consequences in mice2.

Removing a toxic protein from a cell is not a simple task; in fact, it has only been done a handful of times in models of neurodegeneration. One way to eliminate a protein in neurons is to cause the RNA that encodes it to be degraded before it can make the protein. Through a collaboration with a company that specializes in this approach — Ionis Pharmaceuticals — the authors created their own short RNA molecules that matched the sequence and therefore bound to regions in the specific RNA that encodes the protein ataxin 2. These small molecules are known as anti-sense oligonucleotides (ASOs), and once they bind to their partner, they recruit the cell’s waste system to degrade the RNA. Currently, ASO therapy is one of the most promising methods researchers have developed to eliminate toxic proteins for a wide range of degenerative diseases.

blue stethoscope next to laptop computer
Image of stethoscope next to a computer. Photo by Negative Space on

After designing many of these molecules, the authors screened 152 different ASOs to determine which were most effective at lowering levels of the toxic protein. ASOs were applied to skin cells that had been donated by SCA2 patients, and levels of mutated ataxin 2 protein were measured. By picking out the designs that caused the greatest decrease in ataxin 2 levels, the authors narrowed down the original group of potential ASOs to give a shortlist of promising candidates. The authors then chose one ASO (ASO7) to test in mouse models of SCA2.

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DNA Damage Repair: A New SCA Disease Paradigm

Written by Dr. Laura Bowie Edited by Dr. Hayley McLoughlin

Researchers use genetics to find new pathways that impact the onset of polyglutamine disease symptoms

The cells of the human body are complex little machines, specifically evolved to fulfill certain roles. Brain cells, or neurons, act differently from skin cells, which, in turn, act differently from muscle cells. The blueprints for all of these cells are encoded in deoxyribonucleic acid (DNA). To carry out the instructions in these cellular blueprints, the DNA must be made into ribonucleic acid (RNA), which carries the instructions from the DNA to the machinery that makes proteins. Proteins are the primary molecules responsible for the structure, function, and regulation of the body’s organs and tissues. A gene is a unit of DNA that encodes instructions for a heritable characteristic – usually, instructions for a making a particular protein. If there is something wrong at the level of the DNA (known as a mutation) then this can translate to a problem at the level of the protein. This could alter the function of a protein in a detrimental manner – possibly even rendering it totally non-functional.

Artist representation of a DNA molecule. Image courtesy of gagnonm1993 on Pixabay.

DNA is made up of smaller building blocks called nucleotides. There are four different nucleotides: cytosine (C), adenine (A), guanine (G), and thymine (T). Polyglutamine diseases, such as the spinocerebellar ataxias (SCAs) and Huntington’s disease (HD), are caused by a CAG triplet repeat gene expansion, which leads to the expansion of a polyglutamine tract in the protein product of this gene (MacDonald et al., 1993; Zoghbi & Orr, 2000). Beyond a certain tract length, known as the disease “threshold,” the length of this expansion is inversely correlated with age at disease onset. In other words, the longer this expansion is, the earlier those carrying the mutation will develop disease symptoms. However, scientists have determined that onset age is not entirely due to repeat length, since individuals with the same repeat length can have different age of disease symptom onset (Tezenas du Montcel et al., 2014; Wexler et al., 2004). Therefore, other factors must be involved. These factors could be environmental, genetic, or some combination of both.

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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

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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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