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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Blurred lines: how spinocerebellar ataxia type 7 impacts vision

Written by Siddharth Nath Edited by Dr. Ray Truant

Spinocerebellar ataxia type 7 (SCA7) is unique amongst the SCAs in that it involves an organ besides the brain – the eye. Rather than problems with movement, the first hint that something may be wrong for SCA7 patients is often a subtle change in vision. Research done by Dr. Al La Spada in the early 2000s helps explain how and why this happens. 

It’s not all in your head

The spinocerebellar ataxias (SCAs) are, for the most part, similar in how they affect the body. They cause disordered movement (ataxia), trouble with speech (dysarthria), trouble swallowing (dysphagia), and other neurological symptoms. This holds true for all of the polyglutamine-expansion SCAs except for SCA7. In SCA7, doctors have long observed that patients report problems with vision, and in some cases may be entirely blind. Interestingly, these symptoms often appear ahead of any other signs that the patient might have a chronic illness, suggesting that SCA7 affects the eye before it begins to affect the brain.

In the early 2000s, while at the University of Washington, Dr. Al La Spada conducted research into how SCA7 affects the eye. He and his team set out to understand why patients with this disease experience a loss of vision.

Close up photo of a human eye from the side. The eye is hazel in colour.
Close up of a human eye. Photo by Pixabay on Pexels.com

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DNA Damage Repair: A New SCA Disease Paradigm

Written by Dr. Laura Bowie Edited by Dr. Hayley McLoughlin

Researchers use genetics to find new pathways that impact the onset of polyglutamine disease symptoms

The cells of the human body are complex little machines, specifically evolved to fulfill certain roles. Brain cells, or neurons, act differently from skin cells, which, in turn, act differently from muscle cells. The blueprints for all of these cells are encoded in deoxyribonucleic acid (DNA). To carry out the instructions in these cellular blueprints, the DNA must be made into ribonucleic acid (RNA), which carries the instructions from the DNA to the machinery that makes proteins. Proteins are the primary molecules responsible for the structure, function, and regulation of the body’s organs and tissues. A gene is a unit of DNA that encodes instructions for a heritable characteristic – usually, instructions for a making a particular protein. If there is something wrong at the level of the DNA (known as a mutation) then this can translate to a problem at the level of the protein. This could alter the function of a protein in a detrimental manner – possibly even rendering it totally non-functional.

dna-2358911_1280
Artist representation of a DNA molecule. Image courtesy of gagnonm1993 on Pixabay.

DNA is made up of smaller building blocks called nucleotides. There are four different nucleotides: cytosine (C), adenine (A), guanine (G), and thymine (T). Polyglutamine diseases, such as the spinocerebellar ataxias (SCAs) and Huntington’s disease (HD), are caused by a CAG triplet repeat gene expansion, which leads to the expansion of a polyglutamine tract in the protein product of this gene (MacDonald et al., 1993; Zoghbi & Orr, 2000). Beyond a certain tract length, known as the disease “threshold,” the length of this expansion is inversely correlated with age at disease onset. In other words, the longer this expansion is, the earlier those carrying the mutation will develop disease symptoms. However, scientists have determined that onset age is not entirely due to repeat length, since individuals with the same repeat length can have different age of disease symptom onset (Tezenas du Montcel et al., 2014; Wexler et al., 2004). Therefore, other factors must be involved. These factors could be environmental, genetic, or some combination of both.

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Stressed to the limit: Uncovering a role for oxidative stress in spinocerebellar ataxia type 7

Written by Siddharth Nath Edited by Dr. Ray Truant

Oxidative stress is a hot topic in neurodegenerative disease research. New findings from Dr. Jonathan Magaña’s lab in Mexico show increases in measures of damage from oxygen compounds in SCA7 patients versus healthy individuals. This suggests that this type of chemical stress may be a critical step in triggering the death of brain cells in SCA7.

You’re stressed – whether you like it or not

You may not realize it, but all of the cells in your body are, at some point or another, undergoing stress. Now, this isn’t the same as what we normally take the word “stress” to mean. Your cells aren’t cramming for an exam, nor are they worried about an upcoming job interview. Instead, stress at the cellular level refers to the challenges cells face in the form of environmental extremes (like temperature changes), mechanical damage, exposure to toxins, and dysregulation of stress responses.

A particularly nasty type of stress that cells must contend with is oxidative stress. This results from an imbalance in the levels of reactive oxygen species (hence the term ‘oxidative’) within a cell and the cell’s ability to clear away these species. Reactive oxygen species form inside of cells as a byproduct of normal metabolism, and every cell has mechanisms to help with their clearance. These mechanisms, however, can become impaired. This could end up being disastrous because, when not removed properly, reactive oxygen species can wreak havoc in the cell: they have the ability to directly damage every cellular component, including proteins, lipids, and DNA.

red pencil writing the word stress
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Interestingly, oxidative stress increases naturally as we age and is a normal part of growing older. Oxidative stress is a topic of intense study and has been implicated in everything from cancer and bone disease to other neurodegenerative disorders (such as Alzheimer’s disease and Huntington’s disease). An inability to cope with or respond to increases in oxidative stress associated with aging may explain why many neurodegenerative disorders occur later in life, despite the fact that affected individuals express the disease gene from birth.

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