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
Photo by Pedro Figueras on Pexels.com

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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RNA-binding Protein Found to Play a Role in SCA2 Neurodegeneration

Written by Dr. Hayley McLoughlin Edited by Dr. Gülin Öz

Is Staufen1 a kink in the SCA2 toxicity chain that can be exploited?

When a cell is stressed, it can initiate a mechanism to protect messenger RNAs (mRNAs) from harmful conditions.  It does this by segregating the mRNAs, then packaging them up in droplets known as RNA stress granules. ATXN2, the protein that is mutated in SCA2, has previously been reported as a key component in the formation of these RNA stress granules (Nonhoff et al., 2007).  This observation has led researchers to take a closer look at stress granule components, especially in the context of SCA2 disease tissues.

close of of chain with metal links
Image of a metal chain. If a “weak link” is found in the chain of events that go amiss in SCA2, scientists could focus on this area to research possible treatment.  Photo by Pixabay on Pexels.com

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Molecular Mechanism behind Purkinje Cell Toxicity in SCA1 Uncovered

Written by Dr. Chandrakanth Edamakanti   Edited by Dr. Hayley McLoughlin

Recent study decodes the protein signature of toxic Purkinje cells, finding that Purkinje cell mTORC1 signaling is impaired in SCA1.

Spinocerebellar ataxia type 1 (SCA1) is a late onset cerebellar neurodegenerative disorder caused by a mutation (in this case, an abnormal polyglutamine stretch) in the Ataxin-1 gene. People with this condition experience problems with coordination and balance, a set of symptoms known as ataxia. The protein produced by this faulty gene, ATXN1, is particularly toxic to the Purkinje cells, the sole output neurons of the cerebellum. However, the reason behind the selective toxicity of Purkinje cells in SCA1 is unknown.

The main focus of this article is to address this question. It is the first study to find the protein signature of toxic Purkinje cells in SCA1 mice. In the end, the authors identified widespread protein changes that are associated with Purkinje cell toxicity.

science laboratory
Image of scientific laboratory. Photo by Martin Lopez on Pexels.com

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Accidental discovery reveals possible link between cerebellar function and motivation

Written by Logan Morrison Edited by Dr. Sriram Jayabal

Stanford researchers accidentally discover a new role (reward prediction) for the cerebellum, the primary brain region affected by spinocerebellar ataxias.

Would you believe that the part of your brain that enables you to perform simple, everyday tasks (like jogging or walking) also controls your ability to do more complex tasks (like throwing a curve ball) with accuracy? It’s true! Every one of our body’s movements is adjusted by a brain region known as the cerebellum – a primary area of pathology in spinocerebellar ataxias. The name “cerebellum” is a combination of the Latin word for the brain – cerebrum – and the Latin suffix -ellus, which means small. While this “little brain” might not take up much room, it actually contains the vast majority of the nerve cells (known as neurons) in the central nervous system1. Take a look at the image included with this article to see for yourself: even without the red highlighting, the cerebellum should be instantly recognizable as the distinctive structure in the bottom right, so folded and densely-packed that it looks a bit like something you’d find on the branches of a fern or shrub. Among these many folds are the circuits that fine-tune our motor output, providing us with the ability to move our bodies with ease and precision.

Wagner et al image
MRI of human brain, with cerebellum circled in red. Image courtesy of the Central Nervous System – Visual Perspectives Project at Stanford University/Karolinska Institutet2

For decades, not much else was said about the function of the cerebellum beyond its primary role in tweaking movement. Recently, though, there have been some hints that there is more to this part of the brain than we might have thought: brain imaging studies of patients suffering from bipolar disorder, for instance, have sometimes shown abnormalities in the cerebellum3, 4. Cerebellar abnormalities have been implicated in a variety of other diseases, as well, including autism spectrum disorders, schizophrenia, Alzheimer’s disease, and multiple sclerosis5, 6. Now, thanks to the hard work of scientists at Stanford University7 – as well as a bit of luck – we know that the cerebellum is not only involved in how we move, but why.

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The Discovery of SCA8

Written by Dr. Hannah K Shorrock Edited by Dr. Judit M Perez Ortiz

How one team uncovered the first SCA known to be caused by a CTG repeat expansion mutation

Identifying the gene that causes a type of ataxia not only gives patients and their families a clearer diagnosis and prognosis, but also allows scientists to model the disease. Through genetic animal models of ataxia, researchers can study how a single mutation causes a disease and how we can try to slow, halt, or even reverse this process. It is this path through research that may eventually lead from gene discovery to the development of effective therapies.

The gene that causes spinocerebellar ataxia type 8 (SCA8) was first described in a research article published in 1999. Since then, many research articles on SCA8 have been published, including research into the DNA repeat expansions that cause the ataxia, the cellular processes that lead to ataxia, and the development of multiple animal models of SCA8. Together, these move the scientific community further along the road of research.

mother with her two children looking at a mountain
Image of mother with her children. SCA8 was initially identified in a mother and daughter. SCA8 also shows maternal penetrance bias. Photo by Josh Willink on Pexels.com

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