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!
A biomarker is any biological-based measurement that provides useful information regarding a person’s health. For example, blood test results showing increased glucose levels can be used as a biomarker for diabetes. A blood test showing an increased white blood cell count is a biomarker for infection. There are many sources of biomarkers beyond blood biomarkers. MRI, CT, and x-ray scans are all examples of imaging biomarkers. Scored motor assessments can also be used as biomarkers. For example, police use the field sobriety test as a biomarker for alcohol consumption.
Biomarkers can be used to:
Diagnose an existing disease or predict a patient’s prognosis.
Track disease progression.
Determine whether experimental drugs prevent, improve, or slow progression of disease within clinical trials.
What are current biomarkers for spinocerebellar ataxias (SCAs)?
There are multiple biomarkers that are commonly used for patients with ataxia. DNA sequencing from saliva or blood samples of undiagnosed patients with ataxia symptoms can be used to diagnose or rule out SCAs caused by known genetic mutations. The Scale for the Assessment and Rating of Ataxia (SARA) scoring is a common motor assessment used to measure and track severity of ataxia-related balance and coordination issues in patients. MRI scans and other brain imaging techniques can be used to examine brain abnormalities or loss of brain cells.
Why do we need better biomarkers for SCAs?
In an ideal clinical trial, a patient would receive the potential treatment and then undergo a simple assessment (i.e. give a blood sample) shortly after that could conclusively determine whether the drug is working. Thankfully, many potential ataxia treatments are currently in development or are already being tested in clinical trials for patients with SCAs. Unfortunately, we currently do not have an easy, cheap, and sensitive way to measure whether ataxia symptoms are worsening or improving in a relatively short amount of time.
How can we identify better biomarkers for the SCAs?
Researchers are actively seeking better biomarkers for SCAs in animal and cell models of ataxia. There are also multiple ongoing “Natural History” and biomarker clinical trials that focus on different types of SCA diseases. These clinical studies aim to improve our understanding of the SCAs and identify new biomarkers to improve ataxia diagnosis and drug development. These studies may track patients over months or years, and can involve multiple tests, including blood or cerebrospinal fluid samples, brain imaging, or SARA scoring.
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.
Coordination of smooth and effective movements is essential in daily tasks, such as speaking or walking. The ability to successfully orchestrate these movements is commonly referred to as “motor coordination”. While SCA patients can generally initiate movements with their bodies, their ability to execute these in a smooth and precise fashion is impaired. For instance, motor incoordination can be seen in a patient with ataxia’s inability to walk in a straight line, or in the difficulty they experience when swallowing. These and other motor function problems can greatly impact daily life. Assessing how well a patient can perform these movements provides an indication of how affected they are by the disease.
Unlike what’s measured with more familiar medical tests, such as blood pressure or levels of blood sugar, human movement cannot be quantified easily with clear numbers. To address this, multiple rates scales have been developed to help measure standardize motor coordination examinations. One of these scales is the Scale for the Assessment and Rating of Ataxia (SARA). An experienced clinician (typically a neurologist) evaluates a patient’s ability to perform a series of tasks (such as standing and walking) and then, using the SARA, assigns a score for each task. The process takes about 15-20 minutes, and typically involves the following tests:
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.