New Strategy for Reducing Ataxin-1 Levels Shows Promise

Written by Carrie A. Sheeler Edited by Dr. Ronald A.M. Buijsen

RNAi reduces levels of disease-causing Ataxin-1 in SCA1 model mice, easing symptoms of disease when injected both before and after symptom onset.

Lowering the amount of the disease-causing mutant Ataxin-1 protein in affected cells and tissues improves symptoms of disease in spinocerebellar ataxia type 1 (SCA1) mouse models. Like patients with SCA1, mouse models exhibit worsening coordination and degeneration of neurons, beginning in adulthood. Previous work has used genetic manipulation before disease onset (Zu et al 2004). This prevents or delays the onset of disease in SCA1 mouse models. When this is done soon after the onset of symptoms, associated markers of disease are reversed. This suggests that there is a window of time after symptoms start wherein mutant Ataxin-1 can be targeted to improve patient outlook. The 2016 paper by Keiser and colleagues seeks to further study this effect, using RNA interference as a strategy to reduce disease-causing levels of Ataxin-1. As there is no current treatment for Ataxin-1, this is an important step towards assessing possible treatment strategies that could be useful in patients.

female scientist holding a clipboard standing in a laboratory in fornt of a microscope. Books and pictures of neurons line the wall behind her
Cartoon of a scientist reading over results.

Current strategies seek to decrease the amount of Ataxin-1 made in cells by targeting messenger RNA (mRNA)- the blueprints for proteins in a cell- for destruction. RNA interference (RNAi) is one such method which harnesses normal cellular processes to degrade specific mRNAs. In Keiser’s 2016 paper, a modified virus carrying a short sequence of DNA is injected into the brain of a mouse with SCA1. When this virus is injected, the DNA sequence enters the cells of nearby brain regions and stops the production of specific mRNA. In this case, it is Ataxin-1 mRNA that is specifically targeted. As Ataxin-1 mRNA are destroyed, the amount of Ataxin-1 protein made in the cell decreases.

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Huntingtin: a new player in the DNA repair arsenal

Written by Dr. Ambika Tewari Edited by Dr. Mónica Bañez-Coronel

Mutations in the Huntingtin protein impair DNA repair causing significant DNA damage and altered gene expression

Our genome houses the entirety of our genetic material which contains the instructions for making the proteins that are essential for all processes in the body. Each cell within our body, from skin cells that provide a crucial protective barrier, immune cells that protect us from invading species and brain cells that allow us to perceive and communicate with the world contains genetic material. During early development in every mammalian species, there is a massive proliferation of cells that allows the development from a one-cell stage embryo to a functional body containing trillions of cells. For this process to occur efficiently and reliably, the instructions contained in our genetic material need to be precisely transmitted during cell division and its integrity maintained during the cell’s life-span to guarantee its proper functioning.

There are many obstacles that hamper the intricate and highly orchestrated sequence of events during development and aging, causing alterations that can lead to cell dysfunction and disease. Internal and external sources of DNA damage constantly bombard the genome. Examples of external sources include ultraviolet radiation and exposure to chemical agents, while internal sources include cell processes that can arise, for example, from the reactive byproducts of metabolism. Fortunately, nature has evolved a special group of proteins known as DNA damage and repair proteins that act as surveyors to detect erroneous messages. These specialized proteins ensure that damage to the DNA molecules that encode our genetic information is not passed to the new generation of cells during cell division or during the expression of our genes, ultimately protecting our genome. Many genetic disorders are caused by mutations in the genetic material. This leads to a dysfunctional RNA or protein with little or no function (loss of function) or an RNA or protein with an entirely new function (gain of function). Since DNA repair proteins play a crucial role in identifying and targeting mistakes made in the message, it stands to reason that impairment in the DNA repair process might lead to disease. In this study, Rui Gao and colleagues through an extensive collaboration sought to understand the connection between altered DNA repair and Huntington’s disease.

Blue strands of DNA
An artist’s rendering of DNA molecules.

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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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Zapping the brain to help ataxia

Written by Dr. Judit M. Perez Ortiz Edited by Dr. Sriram Jayabal

In a new study, scientists have found that “zapping” the brain with an electromagnetic wand may someday help patients with spinocerebellar ataxia.

In an era of ever-evolving technological advances used for personal entertainment and space travel, medical scientists are harnessing the power of electromagnetism to safely penetrate the skull and manipulate brain cells by mimicking their favorite language – electric current.

Clinicians currently have access to powerful and effective tools designed to stimulate brain cells (known as neurons) for various neurological and psychiatric conditions. Spinocerebellar ataxias (SCAs), however, are not yet in the mix. Though several techniques exist, the methods used to stimulate neurons in the brain can be broadly classified into invasive and non-invasive approaches. For instance, Vagus Nerve Stimulation is used for drug-resistant epileptic seizures, while Deep Brain Stimulation is used for Parkinson’s disease and severe depression. In both instances, a surgical procedure is required because the implanted electrodes have to come in direct contact with the target nerve or brain structure. Disadvantages associated with these surgical methods include the risk of infection, bleeding, and hardware malfunction. Non-invasive approaches to stimulate the brain include electroconvulsive (“shock”) therapy, in which electrodes are placed on the scalp surface to provoke a controlled seizure that yields a therapeutic effect. However, shock therapy requires anesthesia, and patients run the risk of memory issues as a side effect. A second non-invasive brain stimulation tool is also available, called repetitive Transcranial Magnetic Stimulation (rTMS). There are many factors that make rTMS clinically appealing: it does not require surgery, it is already FDA-approved (for severe depression), it is painless, and it has been found to be safe. Further, unlike the broad brain stimulation achieved by electroshock therapy, rTMS delivers a more precise stimulation in a defined brain region, which leaves untargeted brain regions untouched.

cartoon of neuronal brain cells and electricity flowing between them
Artist’s depiction of electrical signals in the brain. Image courtesy of flickr.

Besides its circular or figure-eight attachment, the rTMS device looks quite a bit like a magic wand. Though this is no wizard’s tool, you could say that it does cast a powerful spell: the attachments on the end of the rTMS device are electromagnetic coils, which have the power to “zap” specific brain regions. In a remarkably simple procedure, the wand is gently placed over the patient’s scalp, where it delivers electromagnetic pulses that create just enough electric current to stimulate underlying brain cells without adversely affecting them.

A new pilot study conducted at the Beth Israel Deaconess Medical Center found that using rTMS to stimulate the cerebellum of SCA patients is safe and may improve some aspects of ataxia. First, the investigators recorded the study participants’ baseline movement performance using a battery of tests designed to evaluate different features of ataxia, including balance, gait, and posture. Then, half of the study participants were randomly assigned to receive rTMS, while the other half were assigned to the control, or “sham” group.

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Recovering Purkinje cell health could improve quality of life in SCA3

Written by Jorge Diogo Da Silva Edited by Dr. David Bushart

Normalizing neuronal dysfunction in SCA3/MJD by activating a receptor inside cells

Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease (MJD), is an inherited neurodegenerative disease that typically begins in mid-adulthood. This disease causes loss of coordination and balance (a group of symptoms known as ataxia), abnormal eye movements, and other motor symptoms, all of which limit a patient’s daily life activities. Treating SCA3 patients is currently very challenging, since there are no drugs or other treatments that slow or stop the progression of this disease. While several therapeutic options have been tested in clinical trials, none have shown considerable and consistent effects in improving disease symptoms. Therefore, it is imperative that other treatments are investigated and tested in the clinical setting, in the hopes that we might find a way to improve the lives of SCA3 patients.

The cause of this disease is very well-characterized: patients with SCA3 have an abnormal form of a protein called ataxin-3. All proteins are made up of a sequence of several smaller building blocks known as amino acids. In ataxin-3’s sequence, there is a region where one type of amino acid, glutamine, is repeated consecutively. SCA3 arises when the number of these repeated amino acids is very high (an abnormality known as a polyglutamine expansion), which is toxic for cells.

One of the regions of the brain that is most responsible for regulating balance and movement coordination is the cerebellum, which is located just behind the brainstem (the region connecting the spinal cord to the rest of the brain). As expected, the cerebellum is one of the most affected brain regions in SCA3, since it helps control gait and coordination. Purkinje cells, which are some of the largest neurons in the brain, make up a substantial portion of the cerebellum. These cells receive information from other neurons that detect our surroundings, then emit a signal to the brain regions that control muscles and regulate our movement. This allows us to make movements that are coherent and fluid.

cross section of the cerebellum with purkinje cells stained blue
Cerebellum Cross Section with Purkinje Cells. Image courtesy of Berkshire Community College Bioscience Image Library

Since Purkinje cells are dysfunctional in SCA3, it is reasonable to think that improving the well-being of these cells could also reduce symptoms. In a recent publication, Watanave and colleagues described how they explored a strategy to improve Purkinje cell function using drugs in a mouse model of SCA3, with findings that could be relevant for future studies in patients.

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