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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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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VEGF-mimicking nanoparticles improve SCA1 disease phenotype in mice

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.

stethoscope and blood pressure cuff
Photo by Pixabay on Pexels.com

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.

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A Combined Approach to Treatment: Targeting PAKs in SCA1

Written by Carrie A. Sheeler  Edited by Dr. Marija Cvetanovic

Group 1 p21-associated kinases (PAKs) present a new avenue for SCA1 research.

Spinocerebellar ataxia type 1 (SCA1) is caused by a specific mutation in the Ataxin1 gene, which causes the protein that’s made from that gene (also called Ataxin1) to have an abnormally elongated polyglutamine (polyQ) tract. This leads to dysfunction and death in the affected cells of the brain (predominantly Purkinje neurons in the cerebellum), which causes symptoms in patients that include a progressive worsening of coordination and balance. While there is currently no cure for SCA1, several studies suggest that lowering the amount of Ataxin1 protein in the brain may delay the onset of the disease and decrease the severity of symptoms. This leads us to an important question: how do we most effectively decrease the amount of Ataxin1 in SCA1 patients? One paper recently published by Bondar and colleagues suggests that a multi-pronged approach could be the most effective means of reducing this toxic protein.

close up of two people shaking hands
Evidence suggests combining two potential treatments has a greater impact than each treatment on its own. Photo by rawpixel.com on Pexels.com

The amount of any specific protein in the body can be altered by either decreasing the amount of protein produced or increasing the rate at which cells break those proteins down. Proteins are made using messenger RNA (mRNA), which is created following specific instructions found in DNA. Decreasing the production or stability of mRNA decreases the amount of corresponding protein made. One way to target the mRNA that causes production of a specific protein is with antisense oligonucleotides (ASOs). ASOs are designed to target specific mRNA sequences by binding to them directly. Binding of ASOs to mRNA causes those molecules to be marked for destruction within the cell. Proteins in the body are also regularly recycled, but without the blueprints to build a new protein, cells cannot replenish the protein supply it loses over time. So, if Ataxin1 mRNAs are targeted and destroyed by ASO treatment, the amount of Ataxin1 in our cells would theoretically decrease.

Some proteins can also be altered by other proteins, creating another way that their stability, shape, and function can be regulated. This leads us to the other way we can alter the amount of a specific protein in a cell: regulating the regulators. In terms of SCA1, this could mean removing a protein that helps stabilize Ataxin1 or increasing the production of a protein that breaks Ataxin1 down. Previous research has identified several proteins of interest that regulate Ataxin1 protein stability, including several kinases. Kinases are a class of proteins that transfer a phosphate group from adenosine triphosphate (ATP) to another protein in the cell. The addition of this phosphate group acts as an energy source to the receiving protein, altering its stability or how it interacts with other molecules in the cell (usually by causing it to change its shape). Recently, Bondar and colleagues have identified a new potential regulator of Ataxin1: a group of proteins known as p21-activated kinases (PAKs) (Bondar et al 2018).

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Mitochondrial Dysfunction Found in SCA1 Purkinje Cells

Written by Dr. Terri M Driessen Edited by Dr. David Bushart

Mitochondrial dysfunction and loss of mitochondrial DNA is identified in an SCA1 mouse model.

Spinocerebellar ataxia type 1 (SCA1) is a neurodegenerative disorder that causes cell death in certain parts of the brain. The brain regions affected play important roles in motor coordination. The loss of coordination and movement – a symptom called ataxia – is the one of the primary effects of this disease. To investigate the causes of SCAs, researchers often use mouse models. In mouse models of SCA1, there are deficits in motor coordination before a significant amount of neurons (i.e., brain cells) are lost. This suggests that changes in neuron function, and not necessarily neuron death, may cause behavioral changes in SCA1. However, the mechanisms that cause dysfunction in SCA1 neurons are still a mystery.

Diagram of neuron, highlighting the nucleus, cytoplasm, golgi apparatus, membrane, mitochondria, microtubules, myelin sheath, lysosome, smooth ER, rough ER, dendritic spines, and dendrite.
Image courtesy of Blausen Medical on Wikimedia Commons.

The brain requires a lot of energy to function. Without this energy, our neurons would be unable to survive. The cellular machines that generate this energy are the mitochondria, which are small organelles found in neurons (and nearly every other type of cell, for that matter). If the mitochondria in neurons do not function properly, this could lead to abnormal neuronal functioning. In fact, mitochondrial dysfunction has been found in several neurodegenerative diseases, such as Amyotrophic Lateral Sclerosis (ALS, or Lou Gehrig’s disease), Spinal Muscular Atrophy, Alzheimer’s Disease, Parkinson’s Disease, and Huntington’s Disease. Previous studies have also linked mitochondrial dysfunction to SCA1. It has been shown that Purkinje cells, the major cell type affected in SCA1, have altered levels of mitochondria-related RNA and proteins in SCA1 mouse models (Stucki, et al. 2016; Ferro, et al. 2017).

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