Mitochondrially Stressed

Written by Dr. Judit M. Pérez Ortiz Edited by Dr. Brenda Toscano Márquez

Scientists describe how SCA2 oxidative stress can affect mitochondrial function, and potentially how to fix it

Mitochondrial Stress

We all have experienced stress. When cramming for an exam last minute, or getting ready for a job interview, our bodies feel stress-related energetic drive and hyperfocus. Small bursts of stress can help us get through specific demands, but too much constant stress takes a toll and makes it difficult for us to function. It turns out that the cells in our bodies experience stress too! While the stress response that we experience in our hectic lives is associated with stress hormones, the stress cells experience is from another source altogether – mitochondria. Scientists at the University of Copenhagen in Denmark identified a novel link between mitochondrial oxidative stress and spinocerebellar ataxia type 2 (SCA2).

Classically, we learn that mitochondria are the powerhouse of the cell responsible for making the bulk of the energy currency that cells need to work and survive, ATP. To do this, mitochondria rely on a cooperative group of protein complexes called the Electron Transport Chain (ETC). Albeit via a more sophisticated procedure than a hot-potato game, the complexes mediate chemical reactions (called redox reactions) by which “hot” electrons are passed from high energy molecules to lower-energy molecules, and so on. The final electron recipient (“acceptor”) is a stable oxygen molecule and their encounter is used to make water. The activity of the ETC helps harness energy that is ultimately used to make ATP in what is called oxidative phosphorylation.

Sometimes not all the electrons make it through; the hot potato “drops”. Electrons leak out and react directly with molecular oxygen (chemical formula O2), turning unstable superoxide (chemical formula O2) which in turn, can create other reactive oxygen species (ROS). The extra electron in superoxide gives it a negative charge and makes it highly reactive and toxic. Just like the small amount of stress primes your body for a challenge to come, low levels of ROS hints the cell that it needs to make some changes to optimize the system. As the superoxide levels go up, cells make more antioxidant enzymes available to keep ROS in check. Antioxidant enzymes convert the highly reactive superoxide to a less reactive hydrogen peroxide (like the one in your bathroom cabinet). This, in turn, can be converted to water and ordinary oxygen molecules. In a word, the antioxidants “detox” the cells from ROS insult.

The cell becomes “stressed out” when there’s too much ROS that can’t be compensated for. This stress caused by oxygen or “oxidative stress” can damage DNA, fats, and proteins that affect the cell and organism as a whole. For example, oxidative stress can contribute to heart disease, diabetes, cancer, and neurodegenerative diseases.

cartoon drawing of human cells that are blue
An artist’s drawing of human cells under a microscope.

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In search of a common pathway leading to motor dysfunction in cerebellar ataxias

Written by Dr. Carolyn J. Adamski Edited by Dr. Judit M Perez Ortiz

A research group uncovers a drug target to potentially correct motor phenotypes across several cerebellar ataxias.

When someone is diagnosed with spinocerebellar ataxia (SCA), their symptoms may look very similar despite the fact that different genes are causing the disease. There are over 35 genes known to cause cerebellar ataxia, each of which are studied by scientists to try to understand the ways in which they can each lead to disease. Increasingly, scientists are beginning to appreciate that perhaps it would be helpful to find commonalities between the different SCAs to identify treatment options that could help more SCA patients. The emerging picture is that the genes causing cerebellar ataxia are all vital to the health and function of neurons. Studies like these are currently being conducted all over the world. One group focused on MTSS1, a critical component of neuronal function. They made the exciting discovery that a handful of other genes known to cause cerebellar ataxia were doing so, at least in part, through MTSS1. This study uncovered a common network between cerebellar ataxia genes. Their hope is that someday clinicians will be able to treat many cerebellar ataxias with one therapy.

wooden pole with a wooden arrow pointing to the left
A photo of a road sign giving direction. Could MTSS1 be the pathway sign pointing towards ataxia? Photo by Jens Johnsson on Pexels.com

One approach scientists use to understand a gene’s function is to remove it from the genome, typically in mice, and observe what happens. This group reported that when they removed MTSS1, mice were not able to walk as well as healthy mice. This defect got progressively worse with age. What they observed in these mice looked very similar to what patients with cerebellar ataxia experience. Because there are a few areas of the brain important for walking, the authors wanted to make sure this was due to defects in the cerebellum. Neurons in the cerebellum missing MTSS1 were there, but they were unable to effectively communicate with other neurons in the brain and were slowly dying. When a neuron in the cerebellum fails to communicate the right message, things like poor coordination of body movement happen.

After establishing that removal of MTSS1 causes disease, this group went back to the literature and found that MTSS1 was a fundamental regulator of a pathway known to be critical for communication between neurons. They looked in the mice lacking MTSS1 and found that this pathway was abnormally in “overdrive”. They immediately started looking for ways to correct this. They hoped that by correcting this major pathway, they could help the neurons to more effectively communicate body movements again. Eventually, they found a compound that could specifically dial this pathway down. They gave this drug to the mice lacking MTSS1 and used a number of tests to examine their every movement. To their surprise, they were unable to tell the difference between normal healthy mice and those lacking MTSS1 and treated with the compound. In other words, the compound was able to help the ataxia in these mice. This was an exciting result indeed!

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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 Pexels.com

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.

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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 Pexels.com

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