Written by Dr. By Marija Cvetanovic Edited by Dr.Larissa Nitschke
Suart et al. show that Ataxin-1 interacts with an important DNA repair protein Ataxia telangiectasia mutated (ATM), and that reduction of ATM improves motor phenotype in the fruit fly model of SCA1, indicating DNA repair as an important modifier of SCA1 disease progression.
Each day, due to a combination of wear and tear from the normal processes in the cells, and environmental factors, such as irradiation, DNA in each of our cells can accumulate from 10,000 to 1,000,000 damages. If damaged DNA is left unrepaired, this can lead to loss of cell function, cell death, or a mutation that may facilitate the formation of tumors. To avoid these negative outcomes, cells take care of damaged DNA employing DNA damage response/repair proteins. Ataxia-telangiectasia mutated (ATM) protein is a critical part of DNA repair as it can recognize sites of DNA damage. It also helps recruit other proteins that repair DNA damage.
Mutations in the ATM gene cause autosomal recessive ataxia called Ataxia telangiectasia (AT). AT is characterized by the onset of ataxia in early childhood, prominent blood vessels (telangiectasia), immune deficiency, an increased rate of cancer, and features of early ageing.
Expansion of CAG repeats in the Ataxin-1 gene causes dominantly inherited Spinocerebellar Ataxia Type 1 (SCA1). A feature of SCA1 is that a greater number of repeats correlates to an earlier age of onset of symptoms and worse disease progression. The connection of DNA repair pathways and SCA1 was brought into focus in 2016 by a study by Bettencourt and colleagues. As longer CAG repeat tracts association with earlier ages at onset do not account for all of the difference in the age of onset authors searched for additional genetic modifying factors in a cohort of approximately 1000 patients with SCAs. They showed that DNA repair pathways significantly associate with the age at onset in SCAs, suggesting that genes with roles in the DNA damage response could provide new therapeutic targets (and hence therapeutics) in SCAs.
In this study, Suart et al. identify ATM as one such gene. Using irradiation and oxidizing agent to damage DNA and using imaging to follow ataxin-1 movement, authors first show that ataxin-1 is recruited to the site of DNA damage in cultured cells. They also demonstrate that SCA1 mutation slows down but does not prevent ataxin-1 recruitment to the sites of DNA damage.
What shared research questions is your group investigating?
We use high field, multi-nuclear magnetic resonance imaging (MRI) and spectroscopy (MRS) to explore how diseases impact the central nervous system. These changes can be structural, functional, biochemical and metabolic alterations. For example, we apply advanced MRI and MRS methods in neurodegenerative diseases and diabetes.
We also lead efforts in research taking place at multiple different cities across the United States and the world. As you can imagine, studies spread out across such a big area require a lot of coordination and standardization. We design robust MRI and MRS methods to be used in clinical settings like these.
Another important question for our team is how early microstructural, chemical and functional changes can be detected in the brain and spinal cord by these advanced MR methods. We are interested in looking at these changes across all stages of disease.
Why does your group do this research?
The methods we use (MRI and MRS) can provide very helpful information to be used in clinical trials. These biomarkers we look at can provide quantitative information about how a disease is progressing or changing.
There is good evidence that subtle changes in the brain can be detected by these advanced MR technologies even before patients start having symptoms. If we better understand the earliest changes that are happening in the brain, this can in turn enable interventions at a very early stage. For example, we could treat people even before brain degeneration starts to take place.
Why did you form a research group connecting multiple labs?
We came together to form the CMRR Ataxia Imaging Team to benefit from our shared and complementary expertise, experience, and personnel. We can do more together than we could apart.
Are you recruiting human participants for research?
Our focus is on MR spectroscopy, specifically neurochemistry and metabolism studies. We focus on spinocerebellar ataxias. Also, we have been leading MRS technology harmonization across different sites and vendors.
The Henry Lab
Principal Investigator: Dr. Pierre-Gilles Henry
Year Founded: 2006
We develop advanced methods for MR spectroscopy and motion correction. Then apply these new methods to the study of biochemistry and metabolism in the brain and spinal cord in various diseases. We have been working on ataxias since 2014.
Fun Fact about the Henry Lab: The French language can often be heard in discussions in our lab!
The Lenglet Lab
Principal Investigator: Dr. Christophe Lenglet
Year Founded: 2011
We develop mathematical and computational strategies for human brain and spinal cord connectivity mapping. We do this using high field MRI. Our research aims at better understanding the central nervous system anatomical and functional connectivity. We are especially interested in looking at this in the context of neurological and neurodegenerative diseases.
Members of our team have their roots in 7 countries (US, Turkey, France, India, Mauritius, South Korea, Ghana) and 4 continents (North America, Europe, Asia, Africa)
We study how mishaps and damage in the cerebellum lead to the symptoms experienced by ataxia and tremor patients. By looking at human brains, as well as brains from mouse models, we study how different changes in brain structure can lead to symptoms. This includes how well different parts of the brain can communicate with each other.
Why do you do this research?
When you ask patients about the challenges living with ataxia or tremor, they will talk to you about their symptoms. Symptoms can make different activities of daily living very challenging! By connecting specific brain changes to specific symptoms, we want to develop treatment options that target specific diseases. By doing this, we hope to improve patient’s quality of life.
The Kuo lab is part of the Initiative for Columbia Ataxia and Tremor. It’s a new Initiative at Columbia University to bring a group of physicians, scientists, surgeons, and engineers to advance the knowledge of the cerebellum and to develop effective therapies for ataxia and tremor.
Are you recruiting human participants for research?
Yes, we are! We are looking for participants for clinical research and trials. You can learn more about the studies we are currently recruiting for at this link.
In the Kuo Lab, we call ourselves “the Protector of the Cerebellum in New York City”.
Our laboratory uses multiple methods to explore the underlying causes of different neurodegenerative and neurodevelopmental disorders. Some diseases we study affect children, like Rett Syndrome. Others affect adults, like spinocerebellar ataxia type 1 (SCA1), Alzheimer’s disease (AD) and Parkinson’s disease (PD). We also research how healthy brains grow and develop.
We first seek to understand the mechanism by which a mutant protein causes disease, allowing us to more thoughtfully and effectively develop therapeutic options for the diseases we study. Our work in SCA1 demonstrated that lowering levels of the disease-driving protein is beneficial in the course of disease, informing our approach to the study of other diseases of the brain.
Why do you do this research?
We do this research to help the patients, families and caregivers affected by the diseases we study. Most of the disorders we study currently have no or very few treatment options available, and we hope to help in changing that.
Our lab began with Dr. Zoghbi seeing patients in the clinic who were diagnosed with Rett Syndrome and SCA1. Work with these patients allowed for the discovery of the genes causing these diseases. Today, we hope to aid in understanding how these diseases work and to develop therapies that can then be brought back to the clinic for patients. Furthermore, we hope our findings and the tools we’ve developed will aid in the study of other neurodevelopmental and neurodegenerative disorders.
On April 8, 1993, both Dr. Huda Zoghbi and Dr. Harry Orr identified the gene, ATXN1, which when mutated, is responsible for causing SCA1. You can read about this discovery here.
Neurons are the cells that serve as building blocks of the nervous system. The brain contains an enormous variety of neurons, and they all need to get a start somewhere. The process by which neurons are formed is called neurogenesis.
When does neurogenesis happen?
Nearly all neurogenesis occurs before the age of 2 when the brain is in the early stages of being formed and refined. While most cells in the body are replaced as they wear out or get injured, neurons in the brain do not. By young adulthood, the brain has largely stopped making new neurons. Other than serving as an excellent reason to wear a helmet and otherwise protect your head from injury, this lack of new neuron formation doesn’t have a noticeable effect on how we go about our daily lives. After all, neurons are an incredibly adaptable cell type that readily change in response to a person’s environment and experiences.
In the past few decades, we have learned that there is an exception to the “all neurons are born early in life” rule. Some research has shown that new neurons can, in fact, be formed during adulthood in specific brain areas. For example, the hippocampus, a brain structure important for its role in forming and maintaining memories, continues to create neurons over the course of one’s life.
The purpose of these newly generated neurons is still debated. However, numerous studies have shown that neuron formation in the hippocampus is reduced in instances of psychiatric and neurodegenerative disorders. This includes certain types of ataxia like SCA1. This is thought to contribute to changes in cognitive function and mood, though the exact mechanisms are still being determined.
Why is neurogenesis interesting for the spinocerebellar ataxias (SCAs), aren’t these neurodegenerative disorders?
Since the discovery of neurodegenerative disorders, most research has focused on symptoms and how to delay symptom onset. This view sees neurodegenerative disorders, like the SCAs, as outcomes of mid to late-life when the toxic effects of mutant proteins become suddenly rampant. However, these disorders are caused by proteins that are present from the very earliest stages of brain formation.
In 2018, researchers studying SCA1 found that neurogenesis is increased in the cerebellum of young mice. This changed how the cerebellum communicates with the rest of the brain. This suggests that cerebellar function can be affected by more than neuronal loss. It could be of wider interest in the SCAs given the cerebellar dysfunction that is common between them. No research on cerebellar neurogenesis has been performed in other SCAs by this point. However, there are some indications that neurogenesis may also be altered in SCA2.
Additionally, Huntington’s Disease, a polyglutamine repeat disorder in the same disease family as several SCAs, has been shown to have increased neurogenesis in the cortex in both young mice and prenatal babies. The combination of these recent studies has made early neuron formation an area of key interest in the study of neurodegenerative disorders.
Current theories in the field contend that while the brain can compensate for changes in neuron numbers in early life, altered neurogenesis could be creating unique brain circuitry in individuals with known disorder-causing protein mutations. These changes could make them more vulnerable to neuronal dysfunction and neurodegeneration later in life.
Evidence for changed neurogenesis in SCAs, both early and late in life, adds a new layer of consideration to what we broadly think of as a mid- to late-life neurodegenerative disease. Additional research in coming years will hopefully provide more insight into how these additional facets of neural health may inform the development of new therapies.
Snapshot written by Carrie Sheeler and edited by Dr. Chloe Soutar.
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