We are interested in how the cerebellum influences motor coordination in both the healthy brain and in models of disease and aging. By identifying changes in the cerebellum underlying ataxias and aging, we hope to discover new treatments for patients.
Why do you do this research?
We want to understand how the cerebellum works and use this knowledge to understand the changes in the cerebellum that lead to ataxia. As a lab, we are particularly interested in studying rare disorders like SCA6 and ARSACS.
These disorders have limited treatment options. We hope that by understanding how the cerebellum works differently in these disorders, we will be able to identify new treatments to help ataxia patients.
We are also interested in identifying common changes between different types of ataxia, to find out whether treatments identified in one form of ataxia might also help other ataxia patients.
Fun Lab Fact
We got together and made our own slippers to keep cozy in our office. If you look at the picture closely you might be able to spot some cells from the cerebellum on some of them!
Written by Dr. Amy Smith-Dijak Edited by Logan Morrison
Basic biology helps identify a new treatment for ataxia
Drug design doesn’t always have to start with a blank slate. Sometimes understanding how existing drugs work can help researchers to design new ones, or even to recombine old drugs in new and more effective ways. That’s what the researchers behind this paper did. They investigated the basic biology of three existing drugs: chlorzoxazone, baclofen, and SKA-31.
Two of these – chlorzoxazone and baclofen – are already FDA-approved for use as muscle relaxants, and chlorzoxazone had previously been found to have a positive effect on eye movements in spinocerebellar ataxia type 6. Looking at the results of their experiments, they realized that a combination of chlorzoxazone and baclofen would probably be an effective treatment for ataxia over a long period. They offered this drug combination to patients, who had few adverse effects and showed improvement in their diseasesymptoms. Based on these findings, the researchers recommended that larger trials of this drug combination should be conducted and that people trying to design new drugs to treat ataxia should try to interact with the same targets as chlorzoxazone.
When this paper’s authors started their research, they wanted to know more about how ataxia changes the way that brain cells communicate with each other. Brain cells do this using a code made up of pulses of electricity. They create these pulses by controlling the movement of electrically charged atoms known as ions. The main ions that brain cells use are potassium, sodium, calcium and chloride. Cells control their movement through proteins on their surface called ion channels which allow specific types of ions to travel into or out of the cell at specific times. Different types of cells use different combinations of ion channels, which causes different types of ions to move into and out of the cell more or less easily and under different conditions. This affects how these cells communicate with each other.
For example, a cell’s “excitability” is a measure of how easy it is for that cell to send out electrical pulses. Creating these pulses depends on the right ions entering and exiting the cell at the right time in order to create one of these pulses. Multiple types of spinocerebellar ataxia seem to make it difficult for Purkinje cells, which send information out of the cerebellum, to properly control the pattern of electrical signals that they send out. This would interfere with the cerebellum’s ability to communicate with the rest of the brain. The cerebellum plays an important roll in balance, posture and general motor coordination, so miscommunication between it and the rest of the brain would account for many of the symptoms of spinocerebellar ataxias.
Earlier research had found a link between this disrupted communication and a decrease in the amount of some types of ion channels that let potassium ions into Purkinje cells. Thus, this paper’s authors wanted to see if drugs that made the remaining potassium channels work better would improve Purkinje cell communication.
You may have heard that nerve cells (or neurons) in the brain use electrical activity to communicate with one another. The proteins responsible for creating these electrical signals are called ion channels. How do neurons use these electrical signals to communicate with one another in a meaningful way?
A good way to think about the brain is that it is wired into circuits. These brain circuits are not unlike the electrical circuits that power our home, computers, and cell phones. This means that within these circuits, an individual neuron must be able to send and receive electrical signals to and from its neighbors. The electrical signals used to transmit information down the length of a neuron are called action potentials.
Brain communication: the action potential
Neurons use the electricity harnessed from the opening of ion channels to generate an action potential. Normally, when a neuron is not active, it rests at a negative resting state (or, a hyperpolarized membrane potential). This means that ion channels are closed and the neuron is not actively sending any signals to other neurons. Don’t worry, these voltages aren’t large enough to zap you! Neurons operate in a range between -90 millivolts and +40 millivolts, which is thousands of times smaller than the voltages that power circuits in our homes!
A neuron can become activated with the opening of certain ion channels, particularly ones that allow sodium ions into the neuron. Each time a sodium ion flows into the neuron, the membrane potential becomes slightly more positively charged, or depolarized. Once a specific threshold of depolarization is reached, a huge number of sodium channels open all at once and the cell’s membrane potential moves up to +20 mV.
Interestingly, another major type of ion channel, called a potassium channel, becomes activated on a slight delay compared to when sodium channels open. When potassium channels open, a large amount of positively-charged potassium quickly exits the neuron. This exit of potassium causes the membrane potential returns to its negative resting state. This allows the membrane to become hyperpolarized back to where it began. Now the cycle can start all over when another signal tells the neuron it is time to act. This whole cycle, from -70 mV to +20mV and back again, is the definition of an action potential. Action potentials quickly travel down the neuron in a single direction. Once they reach the end, they help generate a different type of chemical signal that tells the next neuron to generate an action potential of its own. And thus, the information continues to travel through the circuit.
An action potential is an all-or-none response. This means that if the threshold voltage is not reached, the neuron will remain silent and no action potential will be fired. In most neurons, a signal from a neighboring neuron causes the opening of sodium channels to help this signal initiate. However, in certain cell types (such as Purkinje neurons), action potentials can happen spontaneously, and all the time – sometimes even hundreds of times per second!
Why do neuronal action potentials matter for cerebellar ataxia?
Researchers who study mouse models of ataxia have noticed that Purkinje neuron action potentials can undergo big changes during disease. Depending on the type of cerebellar ataxia, Purkinje neuron action potentials may take on a different shape or even disappear completely. Either of these situations could make it difficult, or even impossible, for a neuron to send proper signals to its neighbors. Some researchers suggest that improving action potential firing might be one way to improve ataxia symptoms. For this reason, identifying drugs that improve action potential firing is a major area of therapeutic research in ataxia.
If you would like to learn more about action potential, take a look at these resources by Khan Academy and Wikipedia.
Membrane potential: the electrical voltage of a cell’s outer membrane. Changes in membrane potential are controlled by the opening and closing of many different types of ion channels.
Hyperpolarized: a negatively-charged membrane potential. A neuron usually rests at -70 mV when it is silent. It returns to that voltage after an action potential is completed.
Depolarized: a positively-charged membrane potential. This usually occurs when sodium channels open during the early part of an action potential. This cuases the cell quickly jumps up to +20 mV.
Snapshot written by David Bushart and edited by Celeste Suart.
Written by Frida Niss Edited by Dr. Siddharth Nath
Can neurodegeneration in SCA7 in part be due to faulty calcium homeostasis in the cerebellum?
Polyglutamine diseases are caused by an increase in the length of CAG repeats within a specific gene. The mutation for spinocerebellar ataxia type 7 (SCA7) was discovered more than two decades ago, but many of the details surrounding how the mutation actually causes disease remain fuzzy. We know that the increased repeat length in the gene makes it difficult for the resulting protein to arrange or fold itself properly. We also know that the mutated protein binds to itself and to other proteins in an unusual way. It building up large deposits of seemingly useless debris in the cell, called ‘aggregates’. However, the exact pathways this leads to cell death, and subsequently neurodegeneration, is not completely clear.
There is currently research underway to directly target and inhibit the repeat proteins themselves. However, finding other pathways in the cell that are easier to target with medication is also a priority. In this research, Stoyas and her colleagues wanted to find out more about which cellular pathways are disturbed in the polyglutamine disease SCA7.
SCA7 mice have disordered productions of proteins that help balance ions concentrations
In SCA7, the protein that carries the mutation is Ataxin-7. Ataxin-7 participates in transcription through complexes of proteins that together can change some signalling particles on the DNA. Depending on what signalling particles are attached to a certain gene, the gene is either transcribed and made into a protein, or “silenced” and skipped over. In the case of Ataxin-7 and its complex, they work together to cause transcription of genes. One of the main theories of how a polyglutamine mutation can be toxic in Ataxin-7 is that the mutation disturbs Ataxin-7’s normal function within this transcription activating complex. Instead of being regular and orderly, ataxin-7 starts acting unpredictably. Some things that should be transcribed are not, some that shouldn’t be transcribed are.
What’s cognition got to do with ataxia? Could the cerebellum mediate both cognitive and motor symptoms in the same disease? And how can scientists use mice to find out?
Spinocerebellar ataxia type 1, or SCA1, is a progressive neurodegenerative disease that has no cure. In SCA1, an expanded CAG repeat sequence in the ATXN1 gene increases the chain length of the amino acid glutamine (Q), so SCA1 is called a “polyQ” disease. As suggested by its name, the cerebellum is a heavily affected brain region in SCA1. Since the cerebellum is involved in motor coordination, it is no surprise that dysregulated control of movement, or ataxia, is a major symptom of SCA1.
However, what may come as a surprise is that some SCA1 patients also experience changes in cognition in addition to ataxia. Since the mutated ATXN1 gene is found throughout the brain, it has been difficult to tease apart whether the cerebellum contributes to the cognitive symptoms of SCA1 in addition to the motor symptoms. It is possible that cognitive symptoms of SCA1 might be exclusively caused by brain regions other than the cerebellum. For example, ATXN1 is also highly expressed in the prefrontal cortex, a region known for mediating many cognitive processes. But before we discount the possibility that the cerebellum plays a role in the cognitive symptoms experienced by some SCA1 patients, it is important to note an interesting observation in neuroscience research that has emerged in recent decades. Scientists have described a surprising role of the cerebellum in a host of neurological disorders like autism and schizophrenia. In light of these findings, that the cerebellum could be implicated in both the motor and cognitive symptoms of SCA1 may not be so far-fetched.
A powerful tool on the researcher’s lab bench to study diseases like SCA1 is the laboratory mouse. Since 1902, mice have played an indispensable role in disease research. Scientists can breed mice that express human genes, such as a mutated form of ATXN1, to figure out what goes awry in diseases like SCA1. Animal models of disease help researchers to identify potential treatment strategies that may be useful to humans. Since such in-depth analysis and careful experimental manipulation is impossible in human patients, animal models are an invaluable tool to study diseases like SCA1.
In the SCA1 field, scientists use multiple animal models to study SCA1. Researchers have harnessed the differences between these mouse models to address different questions, such as:
“How does the number of CAG repeats affect SCA1 symptoms in mice?”
“What happens if the ATXN1 gene is removed altogether?”
“Do SCA1 symptoms still occur if the mutant ATXN1 gene is restricted to cerebellar Purkinje cells?
In mice and in humans, we know that the length of the polyQ expansion in the ATXN1 gene correlates with both the severity and the age of symptom onset of SCA1. Mice that express more CAG repeats (a longer polyQ expansion) in their ATXN1 gene experience more severe symptoms that start earlier in life than mice with a shorter polyQ expansion. When mutant ATXN1 expression is restricted to Purkinje cells in the cerebellum, mice display motor impairments similar to what is observed in mice with mutant ATXN1 expression everywhere in the brain. This tells us that disrupting healthy ATXN1 expression in Purkinje cells alone is sufficient to cause motor symptoms that stem from SCA1. To put it plainly, mouse models of SCA1 have been a crucial component of SCA1 research.
Since human SCA1 patients experience behavioral symptoms, scientists also use behavioral tools to evaluate the symptoms of SCA1 mice. Motor coordination tests are essential in ataxia research. These tests allow scientists to determine whether a potential intervention improves or worsens symptoms in mice. This is the first step to evaluate whether an intervention could be promising for human patients. However, as we discussed earlier, motor impairments are not the only symptom faced by SCA1 patients: many exhibit cognitive deficits as well. But could mice be used to evaluate something as complex as cognition? Can laboratory mice really help scientists uncover whether the cerebellum contributes to the cognitive impairments observed in SCA1? Researchers at the University of Minnesota say yes.