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
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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 Creatine-rich Diet Delays Disease in SCA3 Mice

Written by Dr. Lauren R. Moore Edited by Larissa Nitschke

Creatine, a common dietary supplement taken by athletes, delays symptoms and improves balance and strength in SCA3 mice.

Could a common nutritional supplement used by athletes to boost performance also provide benefits to ataxia patients? This was the main question addressed by a recent study of Spinocerebellar Ataxia Type 3 (SCA3), the most common dominantly-inherited ataxia in the world. The study, published in March 2018, was led by Dr. Sara Duarte-Silva at the University of Minho in Portugal. Dr. Duarte-Silva and her team investigated whether feeding SCA3 mice a diet enriched with creatine – a popular dietary supplement – improves the symptoms and brain changes that are associated with SCA3. Researchers found that a high-creatine diet delayed disease and slowed the worsening of symptoms in SCA3 mice. This study provides promising evidence that increasing or adding creatine in daily consumption may have protective benefits for SCA3 patients.

SCA3 is one of six hereditary ataxias caused by a unique type of genetic mutation known as a CAG trinucleotide repeat expansion. This occurs when a repeating sequence of three DNA nucleotides – Cytosine-Adenine-Guanine or “CAG” for short – is expanded, creating an abnormally high number of repeats. In SCA3, mutation occurs in a gene encoding the protein ATXN3 and produces an abnormally long “sticky” region in the disease protein. This sticky region, called a polyglutamine expansion, impairs ATXN3’s normal functions and causes it to build up in brain cells as toxic protein clumps. As a result, the brain’s ability to make and store energy is often impaired in SCA3 patients (a deficit that is also seen in many other brain disorders). Thus, drugs or compounds that improve overall energy production and use in brain cells could be beneficial in SCA3 and other ataxias.

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One such compound that may increase energy efficiency – particularly in the brain and muscles – is creatine. Creatine is made naturally by the body, but can also be consumed through foods like red meats and seafood. In addition, creatine is a common ingredient in many commercially-available dietary supplements that claim to improve athletic performance by boosting energy and building muscle. Creatine has recently been shown to have some benefits in mouse models of other brain diseases with similarities to SCA3. However, whether creatine could benefit SCA3 patients hadn’t been investigated prior to this study.

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Snapshot: What are Mouse Models?

If you are thinking of a dressed-up mouse walking on a ramp and posing for pictures, then you are thinking wrong! Mouse models – as the name indicates – serve as a “model” for human diseases. Mice, similar to many mammals, can develop diseases. These include cancers, diabetes, and cardiovascular problems. Over the past century, mice have been used to study not only these naturally-occurring mouse diseases, but also disorders which do not typically affect mice. For instance, thanks to advancements in genetic engineering, scientists have generated mice that develop Alzheimer’s disease and cystic fibrosis. These mouse models are then used as tools to help scientists study the underlying causes of human diseases and, ultimately, create better treatments.

gloved hands holding a white mouse with red eyes
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Why can’t we study the disease in humans?

In humans, we can only obtain a snapshot of disease at a given time. This is particularly true for neurodegenerative diseases, where one cannot simply isolate parts of the brain to study them. In addition, an individual suffering from neurodegenerative disease is often not aware of their condition – and are not even diagnosed – until they are symptomatic. As a result, it is impossible to understand how an individual developed the disease over time, which can make it quite difficult to determine a proper therapeutic course. To best understand the cause and progression of neurodegenerative disorders, researchers generate animal models. These models, often using mice, are informed by genetic susceptibility and environmental risk and mimic the clinical course of a human disease.

Why use a mouse as a model?

There are several advantages to using the mouse as a model:

  • Humans share more than 95% of their genome with mice, which means disease-causing mutations in mice have an effect that is similar to what occurs in human disease.
  • The mouse genome is well-studied and completely mapped (i.e., all genes have been identified), which makes it easier for researchers to manipulate genes in mice to study most human diseases.
  • The life span of mice is short, which allows the disease to be studied at an accelerated pace.
  • The size and ease in handling of mice makes preliminary testing of potential drug treatments a fairly simple process.
  • The maintenance of mouse models is much cheaper than larger organisms.

Why are mouse models vital?

Mouse models are indispensable for a better understanding of human disease and for the development of effective treatments. Mouse models of deafness, for instance, have played a vital role in identifying the specific genes that are responsible for inherited hearing loss. Similarly, mouse models have also enabled scientists to model complex neurological diseases such as Alzheimer’s disease, Huntington’s disease, and several different types of ataxia. These models have greatly improved our understanding of neurodegenerative disease and brought us one step closer to the development of effective treatments. Because of this, the quest to identify a mouse model that mimics every aspect of a human disease – such as a specific type of spinocerebellar ataxia – continues to this day. These mice are instrumental for scientists to develop new treatments for disease and, ultimately, a cure.

If you would like to learn more about mouse mondels, take a look at these resources by the Jackson Laboratory and National Institutes of Health.

Snapshot written by Dr. Sriram Jayabal edited by Dr. Maxime Rousseaux

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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Where Should We Look to Detect SCA3 Pathology and Progression?

Written by Jorge Diogo Da Silva Edited by Dr. Maria do Carmo Costa

Potential drug targets and biomarkers of SCA3/MJD revealed

Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease (MJD), is a debilitating neurodegenerative disease that usually begins in mid-life. The mutation that causes SCA3 leads to the production of an abnormally large stretch in the gene’s encoded protein, ataxin-3. This irregular ataxin-3 becomes dysfunctional and starts to bundle into toxic aggregates in the brain. SCA3 patients experience a lack of movement coordination, especially when it comes to maintaining their balance while standing or walking, which worsens over time. Currently, there is no cure, effective preventive treatment, or method of monitoring the progression of SCA3. While finding a treatment for SCA3 is undoubtedly needed, identifying markers that are only present in individuals that carry the SCA3 mutation is also critical – it allows researchers and clinicians to track how the disease is progressing, even if the carriers do not show disease symptoms. The use of disease markers is especially important in evaluating the effectiveness of a therapeutic agent during the course of a clinical trial (in this case, one that includes pre-symptomatic carriers).

Textbook diagram of brain
Diagram of the human brain. Picture courtesy of Internet Archive Book Images

The protein ataxin-3 plays many roles in cells, including in transcription – the process by which genes (made of DNA) are transformed into RNA, which in turn encodes all the proteins that are essential to maintaining normal body function. Because the abnormally large ataxin-3 is somehow dysfunctional in SCA3, accurate transcription of genes could be affected. Hence, the authors of this study have looked at transcription in several brain regions in a mouse model of SCA3. These mice harbor the human mutant ataxin-3 gene in their DNA and replicate some of the symptoms that patients experience. In general, this kind of investigation can help provide clues for potential therapeutic strategies, which could work by normalizing the transcription of disease-affected genes. In addition, it can allow researchers to better characterize SCA3-affected genes, which could be used to monitor disease progression if one or more of these genes are affected differently at different stages of the disease. The authors also searched for potential dysregulation of other molecules in the blood of these mice, such as sugars and fats, which is another way disease progression could be monitored. This is particularly useful for patients, as a blood test is much less invasive than any kind of brain analysis. Here, researchers tested blood samples of mice at different ages, as well as brain samples from 17.5-month-old mice (roughly equivalent to a 50-year-old human).

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