Mitochondrial impairments identified in SCA7 mouse model and patient cells

Written by Dr. Colleen A. Stoyas Edited by Dr. Monica Banez 

Duke University researchers have found that altered cellular metabolism and mitochondrial dysfunction play a central role in spinocerebellar ataxia type 7 (SCA7), a result that has therapeutic implications for this disease.

Spinocerebellar ataxia type 7 (SCA7) is a dominantly-inherited ataxia characterized by retinal degeneration and cerebellar atrophy. As retinal degeneration advances, patients experience progressive central vision loss. Atrophy (i.e., cell loss) in the cerebellum causes a progressive loss of balance, as the cerebellum is the region of the brain that controls coordinated movement and motor learning. SCA7 patients also experience difficulty speaking and swallowing in later stages of the disease. Symptoms can manifest at any age, though the disease is particularly aggressive when found in infants and children. SCA7 is caused by an expansion mutation in the Ataxin-7 (ATXN7) gene, which produces a protein containing extra repeats of the amino acid glutamine. These additional glutamines make the protein fold in an incorrect shape. Much like an umbrella turned inside-out, this protein, once it loses its shape, does not work in the way it’s meant to. Dr. Albert La Spada has previously shown that the ataxin-7 protein is necessary for the expression of genes that are central to the normal function of the eye – particularly, the retina. Now, his group has provided evidence that abnormal cellular metabolism underlies the brain changes observed in SCA7.

Mice whose brains carry the SCA7 mutation model the juvenile forms of this disease. Using this mouse model, the La Spada group observed changes in the network and physical size of the brain’s mitochondria. Mitochondria are the cell’s “power plants,” and are responsible for the chemical reactions (known as cellular metabolism) that generate the energy our cells need to function. Cellular metabolism is assessed by measuring metabolites, which are the products of these chemical reactions. The La Spada group’s researchers identified dysfunction in the mitochondria in SCA7 due to an underlying decrease in one specific metabolite: NAD+.

microscope and sample slide
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Short for nicotinamide adenine dinucleotide, NAD+ is necessary for proper mitochondrial function. A general reduction of NAD+ occurs as humans age, as well as in a host of other neurodegenerative disorders (many of which exhibit mitochondrial dysfunction). This recent recent by Dr. La Spada and his team has shown that NAD+ is also reduced in mitochondria in SCA7.

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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.

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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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Thrift Store Pharmacy: Repurposing a Multiple Sclerosis drug for use in SCA6

Written by Anna Cook Edited by Dr. Monica Banez

Researchers successfully use an existing multiple sclerosis drug to improve performance in an SCA6 mouse model

Spinocerebellar ataxia type 6 (SCA6) is a rare hereditary movement disorder affecting 5 of every 100,000 people worldwide1. The disease is caused by the expansion of a repeating DNA sequence in the CACNA1A gene. The length of this repeat, which is made up of sequential iterations of the code CAG, is normally variable in length, stretching between 4 and 18 repeats in the healthy population. However, in SCA6 patients, something goes wrong and the CAG repeat in the CACNA1A gene is expanded to have 21-33 repeats, causing dysfunction in the brain and motor symptoms for reasons that are not yet fully understood. SCA6 belongs to the group of disorders called polyglutamine diseases, all of which are caused by CAG expansions in different genes. These include disorders like Huntington’s disease and other spinocerebellar ataxias.

five laboratory mice on a rotarod device to test their balance
Laboratory mice on a rotarod device to test motor coordination skills, similar to one of the experiments conducted in this study. Image courtesy of WikiMedia.

SCA6 onset generally occurs at middle age. The characteristic symptoms are difficulties with motor coordination that progressively get worse as patients get older. Current treatment options are limited to managing symptoms rather than addressing the cause of the disease. However, researchers have recently discovered that the FDA-approved drug 4-AP reduces motor symptoms in a mouse model of SCA6, making the drug a promising candidate for the treatment of the disease in humans.

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Connecting genetic repeats to symptom variability in SCA3/MJD

Written by Terry Suk Edited by Dr. Hayley McLoughlin

In this classic article, researchers describe how CAG repeat number variation can inform differences in the way SCA3/MJD symptoms present.

Machado-Joseph Disease (MJD) was first described in the 1970’s in four families of Azorean descent. However, it was not initially clear that these families had the same disease, since the symptoms they displayed were highly variable. These symptoms included differing degrees of motor incoordination, muscular atrophy (i.e., loss of muscle mass), spasticity, and rigidity. Later, these four diseases were labeled using the single title of MJD due to their similar genetic inheritance and irregularly high symptom variability1.

In the early 1990’s, a group of French families were diagnosed with Spinocerebellar Ataxia Type III (SCA3), a disease that appeared similar to SCA1 and SCA2 but was shown to be caused by distinct genetic mutation. The symptoms of SCA3 were similar to those of MJD and, importantly, also showed a high degree of variability. The major differences between the two diseases, however, were mostly based on geographical origin (Azorean versus French descent) and family history. Thus, these were considered separate diseases, and very few (if any) ataxia researchers studied both.

Small human figurine standing on a map of the world, specifically on top of France
Initial research done by Cancel and colleagues focused on four French families. Photo by slon_dot_pics on

Then, in 1994, MJD-1 was discovered to be the gene responsible for MJD. The disease-causing mutation in MJD-1 was found to be an expansion of a repetitive DNA sequence in the gene, described as “CAG repeats” (CAG = Cytosine, Adenine, and Guanine)2. Around this time, another research group narrowed down the location of the gene responsible for SCA33. Interestingly, this happened to reside in the same area of the genome as MJD‑1, which was appropriately named the “SCA3/MJD region” soon after. As mentioned above, both SCA3 and MJD patients displayed a wide variety of symptoms. This lead one group of researchers, Cancel and colleagues, to ask the following question in their 1995 publication: What is it about the SCA3/MJD region that leads SCA3 and MJD patients to exhibit such broad symptomatic variability?

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