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.
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!
Written by Dr. Colleen A. Stoyas Edited by Dr. Monica Banez
Duke University researchers have found that altered cellular metabolism and mitochondrial dysfunction play a central role in spinocerebellar ataxia type 7 (SCA7), a result that has therapeutic implications for this disease.
Spinocerebellar ataxia type 7 (SCA7) is a dominantly-inherited ataxia characterized by retinal degeneration and cerebellar atrophy. As retinal degeneration advances, patients experience progressive central vision loss. Atrophy (i.e., cell loss) in the cerebellum causes a progressive loss of balance, as the cerebellum is the region of the brain that controls coordinated movement and motor learning. SCA7 patients also experience difficulty speaking and swallowing in later stages of the disease. Symptoms can manifest at any age, though the disease is particularly aggressive when found in infants and children. SCA7 is caused by an expansion mutation in the Ataxin-7 (ATXN7) gene, which produces a protein containing extra repeats of the amino acid glutamine. These additional glutamines make the protein fold in an incorrect shape. Much like an umbrella turned inside-out, this protein, once it loses its shape, does not work in the way it’s meant to. Dr. Albert La Spada has previously shown that the ataxin-7 protein is necessary for the expression of genes that are central to the normal function of the eye – particularly, the retina. Now, his group has provided evidence that abnormal cellular metabolism underlies the brain changes observed in SCA7.
Mice whose brains carry the SCA7 mutation model the juvenile forms of this disease. Using this mouse model, the La Spada group observed changes in the network and physical size of the brain’s mitochondria. Mitochondria are the cell’s “power plants,” and are responsible for the chemical reactions (known as cellular metabolism) that generate the energy our cells need to function. Cellular metabolism is assessed by measuring metabolites, which are the products of these chemical reactions. The La Spada group’s researchers identified dysfunction in the mitochondria in SCA7 due to an underlying decrease in one specific metabolite: NAD+.
Short for nicotinamide adenine dinucleotide, NAD+ is necessary for proper mitochondrial function. A general reduction of NAD+ occurs as humans age, as well as in a host of other neurodegenerative disorders (many of which exhibit mitochondrial dysfunction). This recent recent by Dr. La Spada and his team has shown that NAD+ is also reduced in mitochondria in SCA7.
Written by Dr. Chandrakanth Edamakanti Edited by Dr. David Bushart
VEGF nanoparticles offer a new avenue for developing treatments for SCA1 and other neurodegenerative disorders
Spinocerebellar ataxia type 1 (SCA1) is a neurogenerative disorder with symptoms that typically begin in the third or fourth decade of life. The disease is characterized mainly by motor incoordination that becomes progressively worse with age. Eventually, patients succumb to the disease about fifteen years after onset due to breathing problems. SCA1 is known as a “polyglutamine expansion” disorder, which means it is caused by a glutamine-rich region of a protein becomes abnormally large due to a genetic mutation. In SCA1, the polyglutamine expansion occurs due to a mutation in the ataxin-1 gene (ATXN1), causing the subsequent ataxin-1 protein to have abnormal functions.
Previously, a research team led by Dr. Puneet Opal found that the levels of a protein called VEGF (vascular endothelial growth factor) is reduced in cerebellum of a mouse model of SCA1. The team was able to improve disease symptoms in these mice by restoring VEGF protein levels using two different methods: i) by crossing the SCA1 mice with another strain of mouse that expressed high levels of VEGF, and ii) delivering recombinant protein (rVEGF) into the brains of SCA1 mice (Cvetanovic M et al 2011). However, the researchers noted that it would be challenging to implement the rVEGF delivery strategy for clinical therapy, since one would need to overcome the extreme financial cost and difficulty that comes with using recombinant proteins.
VEGF is crucial for maintaining the microvasculature (small arteries and veins) in the brain and also supports neuronal health and regeneration. Current evidence suggests that VEGF therapy could be beneficial for several neurodegenerative conditions such as stroke, Alzheimer’s disease, Parkinson’s disease, and ALS. Unfortunately, significant impediments have prevented the translation of recombinant VEGF therapy to the clinic. In a recently published ‘Brain’ research article, Dr. Opal and his team sought to address this obstacle by exploring a potential low-cost VEGF treatment strategy known as VEGF peptide mimetics. These peptide mimetics are smaller and simpler molecules that mimic biological compounds; in this case, VEGF. Peptide mimetics are typically smaller than the original molecule (small enough to be considered “nanoparticles”), which helps limit side effects and makes delivery to the target much easier than using recombinant proteins like rVEGF.
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.
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.
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.
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.