A Creatine-rich Diet Delays Disease in SCA3 Mice

Written by Dr. Lauren R. Moore Edited by Larissa Nitschke

Creatine, a common dietary supplement taken by athletes, delays symptoms and improves balance and strength in SCA3 mice.

Could a common nutritional supplement used by athletes to boost performance also provide benefits to ataxia patients? This was the main question addressed by a recent study of Spinocerebellar Ataxia Type 3 (SCA3), the most common dominantly-inherited ataxia in the world. The study, published in March 2018, was led by Dr. Sara Duarte-Silva at the University of Minho in Portugal. Dr. Duarte-Silva and her team investigated whether feeding SCA3 mice a diet enriched with creatine – a popular dietary supplement – improves the symptoms and brain changes that are associated with SCA3. Researchers found that a high-creatine diet delayed disease and slowed the worsening of symptoms in SCA3 mice. This study provides promising evidence that increasing or adding creatine in daily consumption may have protective benefits for SCA3 patients.

SCA3 is one of six hereditary ataxias caused by a unique type of genetic mutation known as a CAG trinucleotide repeat expansion. This occurs when a repeating sequence of three DNA nucleotides – Cytosine-Adenine-Guanine or “CAG” for short – is expanded, creating an abnormally high number of repeats. In SCA3, mutation occurs in a gene encoding the protein ATXN3 and produces an abnormally long “sticky” region in the disease protein. This sticky region, called a polyglutamine expansion, impairs ATXN3’s normal functions and causes it to build up in brain cells as toxic protein clumps. As a result, the brain’s ability to make and store energy is often impaired in SCA3 patients (a deficit that is also seen in many other brain disorders). Thus, drugs or compounds that improve overall energy production and use in brain cells could be beneficial in SCA3 and other ataxias.

man with white pill in his hand
Photo by rawpixel.com on Pexels.com

One such compound that may increase energy efficiency – particularly in the brain and muscles – is creatine. Creatine is made naturally by the body, but can also be consumed through foods like red meats and seafood. In addition, creatine is a common ingredient in many commercially-available dietary supplements that claim to improve athletic performance by boosting energy and building muscle. Creatine has recently been shown to have some benefits in mouse models of other brain diseases with similarities to SCA3. However, whether creatine could benefit SCA3 patients hadn’t been investigated prior to this study.

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Snapshot: What are Mouse Models?

If you are thinking of a dressed-up mouse walking on a ramp and posing for pictures, then you are thinking wrong! Mouse models – as the name indicates – serve as a “model” for human diseases. Mice, similar to many mammals, can develop diseases. These include cancers, diabetes, and cardiovascular problems. Over the past century, mice have been used to study not only these naturally-occurring mouse diseases, but also disorders which do not typically affect mice. For instance, thanks to advancements in genetic engineering, scientists have generated mice that develop Alzheimer’s disease and cystic fibrosis. These mouse models are then used as tools to help scientists study the underlying causes of human diseases and, ultimately, create better treatments.

gloved hands holding a white mouse with red eyes
Photo by Pixabay on Pexels.com

Why can’t we study the disease in humans?

In humans, we can only obtain a snapshot of disease at a given time. This is particularly true for neurodegenerative diseases, where one cannot simply isolate parts of the brain to study them. In addition, an individual suffering from neurodegenerative disease is often not aware of their condition – and are not even diagnosed – until they are symptomatic. As a result, it is impossible to understand how an individual developed the disease over time, which can make it quite difficult to determine a proper therapeutic course. To best understand the cause and progression of neurodegenerative disorders, researchers generate animal models. These models, often using mice, are informed by genetic susceptibility and environmental risk and mimic the clinical course of a human disease.

Why use a mouse as a model?

There are several advantages to using the mouse as a model:

  • Humans share more than 95% of their genome with mice, which means disease-causing mutations in mice have an effect that is similar to what occurs in human disease.
  • The mouse genome is well-studied and completely mapped (i.e., all genes have been identified), which makes it easier for researchers to manipulate genes in mice to study most human diseases.
  • The life span of mice is short, which allows the disease to be studied at an accelerated pace.
  • The size and ease in handling of mice makes preliminary testing of potential drug treatments a fairly simple process.
  • The maintenance of mouse models is much cheaper than larger organisms.

Why are mouse models vital?

Mouse models are indispensable for a better understanding of human disease and for the development of effective treatments. Mouse models of deafness, for instance, have played a vital role in identifying the specific genes that are responsible for inherited hearing loss. Similarly, mouse models have also enabled scientists to model complex neurological diseases such as Alzheimer’s disease, Huntington’s disease, and several different types of ataxia. These models have greatly improved our understanding of neurodegenerative disease and brought us one step closer to the development of effective treatments. Because of this, the quest to identify a mouse model that mimics every aspect of a human disease – such as a specific type of spinocerebellar ataxia – continues to this day. These mice are instrumental for scientists to develop new treatments for disease and, ultimately, a cure.

If you would like to learn more about mouse mondels, take a look at these resources by the Jackson Laboratory and National Institutes of Health.

Snapshot written by Dr. Sriram Jayabal edited by Dr. Maxime Rousseaux

Thrift Store Pharmacy: Repurposing a Multiple Sclerosis drug for use in SCA6

Written by Anna Cook Edited by Dr. Monica Banez

Researchers successfully use an existing multiple sclerosis drug to improve performance in an SCA6 mouse model

Spinocerebellar ataxia type 6 (SCA6) is a rare hereditary movement disorder affecting 5 of every 100,000 people worldwide1. The disease is caused by the expansion of a repeating DNA sequence in the CACNA1A gene. The length of this repeat, which is made up of sequential iterations of the code CAG, is normally variable in length, stretching between 4 and 18 repeats in the healthy population. However, in SCA6 patients, something goes wrong and the CAG repeat in the CACNA1A gene is expanded to have 21-33 repeats, causing dysfunction in the brain and motor symptoms for reasons that are not yet fully understood. SCA6 belongs to the group of disorders called polyglutamine diseases, all of which are caused by CAG expansions in different genes. These include disorders like Huntington’s disease and other spinocerebellar ataxias.

five laboratory mice on a rotarod device to test their balance
Laboratory mice on a rotarod device to test motor coordination skills, similar to one of the experiments conducted in this study. Image courtesy of WikiMedia.

SCA6 onset generally occurs at middle age. The characteristic symptoms are difficulties with motor coordination that progressively get worse as patients get older. Current treatment options are limited to managing symptoms rather than addressing the cause of the disease. However, researchers have recently discovered that the FDA-approved drug 4-AP reduces motor symptoms in a mouse model of SCA6, making the drug a promising candidate for the treatment of the disease in humans.

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Snapshot: What are Clinical Trials?

How does a medical drug get to patients?

Research is being done every day to discover new or better ways to treat diseases and various medical conditions. In order to determine if these treatments will help patients, studies known as “clinical trials” need to be done before these methods of intervention can be safely and widely used in human patients. Clinical trials are regulated studies that involve volunteer human participants to test how safe and effective a potential new treatment.

doctor writing notes
Physician writing clinical notes. Photo by Pexels.

Treatment interventions being tested can range from medical drugs, to medical devices, to introducing lifestyle changes (diet, exercise). Most clinical trials test new drugs by comparing them to no treatment, to an inactive version of a drug known as a “placebo”, or to a currently available approach. Clinical trials may take months to years to complete and are conducted in a series of steps, known as “phases”, described below.

Phase 1: Is the drug safe?

Healthy volunteers receive different doses of the drug and side effects are evaluated. Safe doses are chosen based on research performed prior to Phase 1, or “pre-clinical research”. The goal is to make sure the drug is not harmful. Usually lasts a few months.

Phase 2: Is the drug effective?

Similar to Phase 1, but the drug is given to a small group of volunteers affected by the medical condition it is intended to treat. This is commonly done by comparing how well participants do with the new drug compared to a placebo. Participants and doctors are typically “blinded”, or prevented from knowing whether the patient received the active drug or the placebo. This is meant to allow for unbiased observations of the participant’s health in response to the drug. Usually lasts a few months to years.

Phase 3: Is the drug still safe? Is it doing what is needed?

Testing becomes a bit more complex. The participant population is expanded while safety and efficacy of the drug continues to be tested. More detailed information about the drug as a treatment is gathered in this phase. Usually lasts several years.

Phase 4: The drug is approved and available on the market.

Long-term effects of the drug will continue to be monitored by pharmaceutical companies and compared to other available drugs and therapies for cost and efficacy.

If you would like to learn more about clinical trials, take a look at these resources by ClinicalTrials.gov and CenterWatch.

Snapshot written by Dr. Claudia Hung edited by Dr. Judit M. Perez Ortiz.

 

 

Connecting genetic repeats to symptom variability in SCA3/MJD

Written by Terry Suk Edited by Dr. Hayley McLoughlin

In this classic article, researchers describe how CAG repeat number variation can inform differences in the way SCA3/MJD symptoms present.

Machado-Joseph Disease (MJD) was first described in the 1970’s in four families of Azorean descent. However, it was not initially clear that these families had the same disease, since the symptoms they displayed were highly variable. These symptoms included differing degrees of motor incoordination, muscular atrophy (i.e., loss of muscle mass), spasticity, and rigidity. Later, these four diseases were labeled using the single title of MJD due to their similar genetic inheritance and irregularly high symptom variability1.

In the early 1990’s, a group of French families were diagnosed with Spinocerebellar Ataxia Type III (SCA3), a disease that appeared similar to SCA1 and SCA2 but was shown to be caused by distinct genetic mutation. The symptoms of SCA3 were similar to those of MJD and, importantly, also showed a high degree of variability. The major differences between the two diseases, however, were mostly based on geographical origin (Azorean versus French descent) and family history. Thus, these were considered separate diseases, and very few (if any) ataxia researchers studied both.

Small human figurine standing on a map of the world, specifically on top of France
Initial research done by Cancel and colleagues focused on four French families. Photo by slon_dot_pics on Pexels.com

Then, in 1994, MJD-1 was discovered to be the gene responsible for MJD. The disease-causing mutation in MJD-1 was found to be an expansion of a repetitive DNA sequence in the gene, described as “CAG repeats” (CAG = Cytosine, Adenine, and Guanine)2. Around this time, another research group narrowed down the location of the gene responsible for SCA33. Interestingly, this happened to reside in the same area of the genome as MJD‑1, which was appropriately named the “SCA3/MJD region” soon after. As mentioned above, both SCA3 and MJD patients displayed a wide variety of symptoms. This lead one group of researchers, Cancel and colleagues, to ask the following question in their 1995 publication: What is it about the SCA3/MJD region that leads SCA3 and MJD patients to exhibit such broad symptomatic variability?

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