Brain-derived neurotrophic factor: A new (old) hope for the treatment of SCA1

Written by Eviatar Fields Edited by Dr. Vitaliy Bondar

Scientists use Brain Derived Neurotrophic Factor to delay motor symptom onset and cell death in a mouse model of Spinocerebellar Ataxia Type 1

Spinocerebellar ataxia type 1 (SCA1) is a rare neurodegenerative disease that affects about 2 out of 100,000 individuals. Patients with SCA1 present with motor symptoms such as disordered walking, poor motor coordination and balance problems by their mid-thirties and will progressively get worse symptoms over the next two decades. No treatments for SCA1 exists. These motor symptoms cause a significant decrease in patient independence and quality of life. Scientists use mouse models that recreate many SCA1 symptoms to understand the cause of this disease and test new treatments.

In this paper, Mellesmoen and colleagues use a mouse model of SCA1 which presents with severe motor symptoms by adulthood. In order to measure the severity of the motor problems in the SCA1 mouse model, the researchers use a test called a rotarod. The rotarod test is similar to a rolling log balance: mice are placed on a rotating drum that slowly accelerates. Mice that can stay on the drum for longer durations have better motor coordination than mice who fall off the drum earlier. Mellesmoen was trying to find a way to get the mice to stay on the drum for longer.

artistic cartoon of male doctor sin from of a microscope and large DNA model
Cartoon of a medical researcher holding a clipboard. 

Purkinje cells, the main cells of the cerebellum, eventually die in SCA1 mouse models and in patients later in life. However, it remains unclear how and why these brain cells, which are responsible for the fine-tuning of movement and motor coordination, die. This is an important question as its answer might lead to new treatments that prevent brain cells from dying which might improve SCA1 symptoms. One possibility is that some changes in gene expression (that is, how “active” or “inactive” a gene is) causes the cells to die in SCA1 mice. To test this hypothesis, the authors used a technique called RNA-seq to examine how gene expression is altered in SCA1 mice compared to healthy mice.

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Snapshot: What is RNA?

RNA is an important molecule that helps with regulating the function of cells. To fully understand how RNA fits in here, we must first look at the bigger picture: genetics. The central dogma of molecular biology, depicted below, states that DNA is copied (transcribed) into RNA, which is later decoded (translated) into proteins, which perform many vital functions in the cell. So, when the cell needs a specific protein, it locates the stretch of DNA that contains the code for this protein and starts to write a copy of that stretch of DNA. This copy is made using RNA, or ribonucleic acid, as a backbone. RNA is very similar to DNA, but contains one extra oxygen atom in the basic building block. Only one strand of the DNA is copied, so RNA ends up looking like half a DNA molecule. The RNA molecule can be seen as the messenger between the archive of your genes (DNA) and the protein production site. However, RNA is very versatile and is also involved in protein regulation, transport of molecules and as a structural component of large complexes in the cell.

The "central dogma" of molecular biology: DNA makes RNA, then RNA makes protein.
The “central dogma” of molecular biology: DNA makes RNA, then RNA makes protein. Adapted from Wikimedia.

The shifting stream of RNA

Apart from small random mutations during the course of a lifetime, the DNA contained in every cell remains the same from birth to death. However, since different cells need different proteins at different stages of growth, there needs to be a selection of which genes are copied and translated into proteins. This means that the process of making RNA has to be very flexible. This flexibility is achieved through a large network of signals that tell the cell which regions of DNA should be transcribed into RNA, and at what rate. To keep up with the demands of the cell, there are millions of RNAs being made at all times, to send out instructions to makes proteins.

How can RNA cause disease?

In some spinocerebellar ataxias, such as e.g. SCA8, the messenger RNA molecules contain long repetitive sequences that become sticky to other copies of the same RNA or to proteins, forming both small and large clumps in the cell. There is still controversy surrounding which steps in the process that ultimately causes cell death in large brain areas, but it seems that unsolicited binding of these sticky RNAs to proteins and other RNAs causes disruption to several functions in the cell simultaneously. Therefore, many researchers are hopeful that reducing the amount of these RNAs in the cell using Antisense Oligonucleotides or RNA interference can help treat spinocerebellar ataxias and other similar diseases.

If you would like to learn more about RNA, take a look at these resources by the Encyclopedia Britannica and Khan Academy.

Snapshot written by Frida Niss and edited by Dr. Hayley McLoughlin.

Discovery in mice sheds light on how the brain learns to adjust how we walk (video)

Written by Dr. Ambika Tewari Edited by Dr. Sriram Jayabal

New research identifies the cell type in the cerebellum that is vital for a specific form of motor learning

Locomotion – the process of moving oneself from one place to another – is highly adaptive. Depending on our current needs, we can alter the way we walk (known as our gait) without much trouble. For instance, we might increase our speed to get to a meeting in time or, if we have time for a more relaxing stroll, reduce our speed. This locomotor adaptation may seem effortless, but it actually involves a high level of coordination. It is quite apparent when witnessing a toddler trying to walk that figuring out our adaptive mechanisms plays an important role in fine-tuning movements. Because of this, determining how locomotor adaptation works has become a focus of research in the field of rehabilitative therapy, especially with patient populations that experiences gait deficits.

Young toddler boy learning how to walk and balance
Photo of a toddler how to walk. How does of brain learn how to fine tune our movements to help us balance? Photo by Aleksandr Balandin on Pexels.com

In an effort to better understand the intricate details of locomotor adaptation, researchers at the University of Portugal recently performed a study using adult mice. In this study, mice performed a task on a specialized piece of equipment called a split-belt treadmill, which consists of two separate belts running parallel to each other. The speed of these belts can be independently controlled, allowing researchers to impose different demands to the limbs on the right side of the body versus the left. Though split-belt treadmills are used in rehabilitative therapy for patients with post-stroke hemiparesis (where one side of the body is weakened after stroke), this was the first study that adapted the use of this treadmill for mice.

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Snapshot: What is Gene Therapy?

Gene therapy is using nucleic acids to treat a genetic disorder.  These nucleic acids can be designed in a variety of ways to achieve the same therapeutic outcome. Gene therapy tools can be used to correct a mutant gene by one of three ways:

  1. Expressing a healthy copy of a gene
  2. Silencing or inactivating the mutant gene transcript
  3. Using genome editing tools to repair or turn-off the mutated gene.
computer desk laptop stethoscope
Photo of a stethoscope by Negative Space on Pexels.com

How is gene therapy used?

Monogenic disorders, like some spinocerebellar ataxias (SCAs), are excellent targets for gene therapy approaches. Gene therapies are currently being used throughout ataxia research for studying disease mechanisms and for preclinical therapeutic application.

Overview of how gene therapy works. First, Package the healthy gene, RNAi, or gene editing tools into the AAV (can also deliver as naked DNA or in a nanoparticle). Second, Inject the packaged AAV into the tissue of interest. Third, AAV will enter the cell and release the genetic material. The cell will become healthy by either 1) expressing the normal gene, 2) repressing the mutant RNA, or by 3) correcting the mutant gene.
Overview of gene therapy, designed by Stephanie Coffin using Biorender.

One gene therapy approach for rescuing SCA1 phenotypes involves overexpressing a healthy gene, ataxin-1-like, which competes with the mutant ATXN1 protein for complex formation. This work, conducted by Keiser and colleagues in 2016, showed phenotypic rescue in a mouse model of SCA1.

There are two common technologies for silencing or inactivating disease genes: RNA interference (RNAi) or antisense oligonucleotides (ASOs). RNAi strategies utilize small RNA molecules to knock down the expression of target mutant RNA transcripts, while ASOs are DNA molecules used to knock down or correct mutant RNA transcripts. Both therapeutic approaches are being pursued in SCAs. For example, Carmo and colleagues in 2013 showed that using RNAi against the SCA3 disease gene, ATXN3, could longitudinally decrease mutant ATXN3 levels. See the SCAsource snapshot on ASOs for further information about their use in SCAs.

The most common genome editing tool is the CRISPR/Cas9 system, which uses an RNA guide to direct the Cas9 nuclease to the region of the genome to be edited. One can then knockout that gene or correct the mutant gene. It is early days for this technology as a potential therapeutic option due to the challenges of delivery and the risk of off-target editing.

How is gene therapy delivered?

One of the most difficult aspects of gene therapy is how to deliver these various molecules to the cells of interest. One of the most common delivery methods is through viral delivery.  The “drug” nucleic acid is transferred into the disease cells by a vector, which is a virus that has been modified to remove viral components. The most common viral vectors for gene therapies currently are adeno-associated viruses (AAVs). Other delivery methods include non-viral vectors such as naked DNA and nanoparticles.

How long-lasting is gene therapy?

Viral delivery of gene therapy products provides a longitudinal expression of the nucleic acid, while naked DNA and nanoparticles express the nucleic acid drug transiently, thus typically requiring ongoing treatment.

If you would like to learn more about gene therapy, take a look at these resources by the National Institutes of Health and KidsHealth.

Snapshot written by Stephanie Coffin and edited by Dr.Hayley McLoughlin.

In search of a common pathway leading to motor dysfunction in cerebellar ataxias

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.

wooden pole with a wooden arrow pointing to the left
A photo of a road sign giving direction. Could MTSS1 be the pathway sign pointing towards ataxia? Photo by Jens Johnsson on Pexels.com

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!

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