Snapshot: What is the Blood-Brain Barrier?

What is the blood-brain barrier?

Blood circulates throughout the body in tubes called blood vessels, delivering oxygen and essential nutrients to different organs. However, not all things that circulate through the body can get into the brain. The blood vessels of the brain are slightly different. Their walls have a unique barrier that allows entry of some substances, but keeps others out of the brain. This unique security feature is known as the blood-brain barrier. This barrier allows passage of some substances, but can block out others. This is important because this provides access to substances that the brain needs to function, while keeping harmful substances at bay. The blood-brain barrier is therefore an important feature that keeps our brains and bodies healthy.

A crossing guard holds a stop sign with a brain on it in one hand. The other hand is held out to say "stop".
The blood-brain barrier is like a crossing guard. It helps some chemicals enter the brain, but it keeps others out.

How does the blood-brain barrier work?

The blood-brain barrier is the result of the coordinated effort of several players working together at a microscopic level. These players form physical and functional barriers to select what can enter or exit the brain. Like other blood vessels in the rest of the body, blood vessels in the brain are lined with a thin wall of cells called endothelial cells. Between these endothelial cells, there are gaps that can allow substances to exit the blood to the various organs in the body. However, in the brain, these cells form tight connections between the gaps to restrict large molecules from passing through.

Additionally, brain cells called astrocytes and pericytes wrap around endothelial cells to more strictly block what substances can get through. Very small molecules, such as hormones, can slip through this complex wall. Larger molecules, such as sugars, water, amino acids, and insulin, require help from proteins known as transporters to get through, and are a critical component of the blood-brain barrier.

What happens if the blood-brain barrier is not working properly?

Infections, abnormal inflammation, or prolonged stress in the body can contribute to larger gaps between the tight connections of the blood-brain barrier, seen in diseases such as multiple sclerosis or Alzheimer’s disease or with brain tumours. If the blood-brain barrier is not working properly, harmful substances that are usually kept out of the brain may enter and cause problems, and can start a harmful cycle of more infections and more inflammation.

What challenge does the blood-brain barrier post for brain therapies?

The blood-brain barrier is critical for regulating what enters or exits the brain to maintain a healthy brain. However, the blood-brain barrier also poses a challenge for researchers. Many potentially life-saving drugs developed for treating brain diseases and brain injury cannot pass through this barrier. To overcome this, scientists have devised novel ways to directly or indirectly deliver drugs into the brain. The therapeutic potential of smaller sized drugs (often called “small molecules”) is intentionally being tested as they can more easily pass from the blood to the brain.

Another alternative is making previously impenetrable drugs better at entering the blood-brain barrier. Scientists are trying to do this by attaching chemical modifications that “escort” them into the brain. Finally, direct access to the brain is created by injections that allow access to the brain space. We will talk more about this topic in our Snapshot on Intrathecal Injections next week!

If you would like to learn more about blood-brain barrier, take a look at these resources by the BrainFacts.org or The University of Queensland.

Snapshot written by Claudia Hung and edited by Judit M. Pérez Ortiz

Targeting protein degradation to alleviate symptoms in MJD

Written by Ambika Tewari   Edited by Brenda Toscano Márquez

Trehalose, a natural autophagy inducer shows promise as a therapeutic candidate for MJD/SCA3

Every cell has an elaborate set of surveillance mechanisms to ensure optimal functioning. As proteins are synthesized, errors can occur leading to misfolded proteins. These abnormal proteins can be harmful to the cell. For this reasons it is important to monitortheir occurrence and decide whether they should be degraded.  Autophagy is one way that these misfolded proteins can be degraded. Autophagy literally means self-eating and serves as a quality control mechanism. Defects in autophagy have been linked to several neurodegenerative disorders.

Machado-Joseph disease (MJD) or spinocerebellar ataxia type 3 is caused by an abnormal expanded CAG repeat in the ATXN3 gene. This CAG expansion causes misfolding of the ataxin-3 protein. The now unstable ataxin-3 is prone to forming aggregates in cells of some regions of the brain including the cerebellum, brainstem and basal ganglia. The accumulation of ataxin-3 in the cell leads to the progressive loss of neurons in the affected brain regions.

Normal ataxin-1 proteins becomes misfolded due to CAG expansion, but autophagy with proteins LC3B and Beclin-1 should degrade and break down misfolded ataxin-3
A diagram of how autophagy should break down abnormal expanded ataxin-3. But what happens when this break down doesn’t happen? Diagram by  Ambika Tewari using BioRender.

Researchers, eager to help patients with MJD, began to question why would the cellular surveillance system allow this toxic accumulation of misfolded ataxin-3. Surely there are mechanisms, like autophagy, to prevent this from occurring. This led to a number of studies that found that autophagy is defective in MJD patients. This was also confirmed in different mouse and cell models of MJD. In fact, earlier studies by the lab of Dr. Luís Pereira de Almeida found that increasing the amount of an autophagy protein (beclin-1) in the brain of an MJD mouse model improved some of the behavioral and neuropathological deficits. Together, these studies have provided evidence that autophagy may serve as a therapeutic target for MJD.

Continue reading “Targeting protein degradation to alleviate symptoms in MJD”

A New Use for Old Drugs

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.

mutliple types of drugs in pill form scattered ac
Can old drugs have potential for new types of treatment? Photo by Anna Shvets on Pexels.com.

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.

Continue reading “A New Use for Old Drugs”

Snapshot: What is Omaveloxolone?

A new therapeutic compound shows promise to treat Friedrich’s ataxia.

What is Friedrich’s ataxia (FA)?

Friedrich’s ataxia is a genetic neurodegenerative disease that affects many organs, most notably nerves, muscles, and heart. FA is a recessive ataxia. Symptoms typically present in childhood and result in significant physical disability. Cognition (thinking, memory) remains intact.

Some of the symptoms a person with FA may experience include ataxia (loss of movement coordination), fatigue, muscle weakness, cardiomyopathy (heart issues), scoliosis (curvature of the spine) and sensory impairments (vision, hearing). Life expectancy is reduced as a result of the disease.

The genetic change that is present in FA affects the production of a protein called frataxin. Frataxin deficiency leads to abnormal iron accumulation in mitochondria.  As mitochondria are critical for energy metabolism and other important functions in cells, their dysfunction causes faulty energy production and undesirable toxicity in the form of reactive oxygen species.

There is currently no treatment available to patients with FA.

white medical pills in the shape of a question mark
What is Omaveloxolone? How could it help people with Friedrich’s Ataxia? Photo by Anna Shvets on Pexels.com

How does Omaveloxolone work?

Omevaloxolone is a synthetic compound. It works by counteracting deficits seen in disease at the cellular level. Omevaloxolone promotes Nrf2, which works to activate a series of defence mechanisms that help cells handle oxidative stress (mentioned above). Nrf2 is also important for improving the energy production machinery mitochondria require to function efficiently. Thus, by activating Nrf2, Omevaloxolone is thought to mitigate oxidative damage, improve energy production, and promote neuroprotection. Additionally, Omevaloxolone and similar compounds exhibit anti-inflammatory action.

What exactly has been validated?

In the MOXIe clinical trial, study participants with FA from several countries were randomized to either daily omaveloxolone (drug) or placebo (control). Their neurological function, activities of daily living, and ataxia were assessed at baseline (at the beginning) and after 48 months of receiving treatment. At the end of this period, the data showed statistically significant improvement in each of these measures. Participants who received omaveloxolone fared better than those who did not (placebo). Additionally, participants who received omaveloxolone saw improvements after treatment compared to their own baseline at the beginning of the study.

What is happening next?

The next step in testing omaveloxolone is to have a long-term study to examine its safety (and any side effects) over the course of a few years. Instead of having a control group in this type of study, called an open-label extension, now everyone enrolled received the same amount of omaveloxolone. This study is already underway and is expected to be completed by 2022. There have been some modifications to the long-term safety study in response to COVID-19, but Reata doesn’t expect there to be a significant delay in their timelines.

If you would like to learn more about omaveloxolone, take a look at these resources by the Reata Pharmaceuticals and ClinicalTrials.gov. To learn more about Friedrich’s Ataxia, visit the Friedrich’s Ataxia Research Alliance website.

Snapshot written by Dr. Judit M. Pérez Ortiz and edited by Larissa Nitschke.

New molecule can reverse the Huntington’s disease mutation in lab models

Written by Dr. Michael Flower Edited by Dr. Rachel Harding

Editor’s Note: This article was initially published by HDBuzz on March 13, 2020. They have graciously allowed us to build on their work and add a section on how this research may be relevant to ataxia. This additional writing was done by Celeste Suart and edited by David Bushart.

A collaborative team of scientists from Canada and Japan have identified a small molecule which can change the CAG-repeat length in different lab models of Huntington’s disease.

CAG repeats are unstable

Huntington’s disease is caused by a stretch of C, A and G chemical letters in the Huntingtin gene, which are repeated over and over again until the number of repeats passes a critical limit; at least 36 CAG-repeats are needed to result in HD.

In fact, these repeats can be unstable, and carry on getting bigger throughout HD patients’ lives, but the rate of change of the repeat varies in different tissues of the body.

In the blood, the CAG repeat is quite stable, so an HD genetic blood test result remains reliable. But the CAG repeat can expand particularly fast in some deep structures of the brain that are involved in movement, where they can grow to over 1000 CAG repeats. Scientists think that there could be a correlation between repeat expansion and brain cell degeneration, which might explain why certain brain structures are more vulnerable in HD.

a print out of genetic information show as a list of A,T, C, and G letters
The CAG repeat of the huntingtin gene sequence can be changed to include more and more repeats, in a process called repeat expansion. This can also happens in some ataxia related genes. Image credit: “Gattaca?” by IRGlover is licensed under CC BY-NC 2.0

But why?

This raises the question, what is it that’s causing the CAG repeat to get bigger? It seems to be something to do with DNA repair.

We’re all exposed continually to an onslaught of DNA damage every day, from sunlight and passive smoking, to ageing and what we eat. Over millions of years, we’ve evolved a complex web of DNA repair systems to rapidly repair damage done to our genomes before it can kill our cells or cause cancer. Like all cellular machines, that DNA repair machinery is made by following instructions in certain genes. In effect, our DNA contains the instructions for repairing itself, which is quite trippy but also fairly cool.

What is it that’s causing the CAG repeat to get bigger? 

We’ve known for several years that certain mouse models of HD have less efficient systems to repair their DNA, and those mice have more stable CAG repeats. What’s more, deleting certain DNA repair genes altogether can prevent repeat expansion entirely.

But hang on, isn’t our DNA repair system meant to protect against mutations like these?? Well normally, yes. However, it appears a specific DNA repair system, called mismatch repair, sees the CAG repeat in the huntingtin gene as an error, and tries to repair it, but does a shoddy job and introduces extra repeats.

Why does this matter?

There’s been an explosion of interest in this field recently, largely because huge genetic studies in HD patients have found that several DNA repair genes can affect the age HD symptoms start and the speed at which they progress. One hypothesis to explain these findings is that slowing down repeat expansion slows down the disease. What if we could make a drug that stops, or even reverses repeat expansion? Maybe we could slow down or even prevent HD.

Continue reading “New molecule can reverse the Huntington’s disease mutation in lab models”