SCA3 Archives |

Spotlight: The CMRR Ataxia Imaging Team

Location: University of Minnesota, MN, USA

Year Research Group Founded: 2008

What disease areas do you research?

What models and techniques do you use?

Mouse models
Human Participants
Magnetic Resonance Imaging and Spectroscopy
Brain Connectivity Mapping
Computational & biophysical models of diffusion

A photo of the CMRR Ataxia Imaging Team in 2019. Front row, left to right – Diane Hutter, Christophe Lenglet (PI), Gulin Oz (PI), Katie Gundry, Jayashree Chandrasekaran Back row, left to right: Brian Hanna, James Joers, Pramod Pisharady, Kathryn France, Pierre-Gilles Henry (PI), Dinesh Deelchand, Young Woo Park, Isaac Adanyeguh (insert)

Research Group Focus

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?

Yes, we are! We are looking for participants for multiple different studies. You can learn more about the research we are recruiting for at the following links: READISCA, TRACK-FA, NAF Studies, and FARA Studies. More information is also available through the UMN Ataxia Center.

A photo of the CMRR Ataxia Imaging Team in 2016, in front of the historic 4T scanner where the first functional MR images were obtained, in CMRR courtyard. Left to right – Christophe Lenglet (PI), Sarah Larson, Gulin Oz (PI), Dinesh Deelchand, Pierre-Gilles Henry (PI), James Joers, Diane Hutter

What Labs Make Up the CMRR Ataxia Imaging Team?

The Oz Lab

Principal Investigator: Dr. Gulin Oz

Year Founded: 2006

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.

Fun Fact

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)

For More Information, check out the Center for Magnetic Resonance Research (CMRR) Website!

Written by Dr. Gulin Oz, Dr. Pierre-Gilles Henry, and Dr. Christophe Lenglet, Edited by Celeste Suart

Spotlight: The Kuo Lab

Principal Investigator: Dr. Sheng-Han Kuo

Location: Columbia University, New York, NY, United States

Year Founded: 2012

What disease areas do you research?

What models and techniques do you use?

Mouse models
Post-mortem patient tissue
Optogenetics
Human physiology
EEG (electroencephalogram)
Neuromodulation

Kuo Lab group photo. — This is a group picture of the Kuo Lab. From the left to right: Nadia Amokrane, Chi-Ying (Roy) Lin, Sara Radmard, Sheng-Han Kuo (PI), Chih-Chun (Charles) Lin, Odane Liu, Chun-Lun Ni , Meng-Ling Chen, Natasha Desai, David Ruff.

Research Focus

What is your research about?

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.

Fun Fact

In the Kuo Lab, we call ourselves “the Protector of the Cerebellum in New York City”.

For More Information, check out the Kuo Lab Website!

We are looking for new graduate students and postdoctoral researchers to join our team. If you are interested in our work, please reach out to us

Written by Dr. Sheng-Han Kuo, Edited by Celeste Suart

Failure to repair DNA damage may be linked to SCA3

Written by Dr. Ambika Tewari Edited by Dr. Maria do Carmo Costa

Mutations in Ataxin-3 protein prevent the normal functioning of a DNA repair enzyme leading to an accumulation of errors

Cells are bombarded by thousands of DNA damaging events each day from internal and external sources. Internal sources include routine processes that occur within cells that generate reactive byproducts, while external sources include ultraviolet radiation. This DNA damage can be detrimental to cells. But the coordination of many DNA repair proteins helps to maintain the integrity of the genome. This prevent the accumulation of mutations that can lead to cancer.

DNA repair proteins play very important roles in the nervous system. During development, cells are actively growing and dividing and can incur many errors during these processes. Therefore, it is not surprising that numerous DNA repair proteins are expressed in the mammalian brain to prevent the accumulation of DNA damage. To much DNA damage can produce devastating consequences.

Damaged DNA molecule — Ataxin-3 plays a role in a DNA repair pathway which fixes double-strand DNA break. If these breaks are not fixed, there are devastating consequences. Photo used under license by Rost9/Shutterstock.com.

In fact, DNA repair deficiencies usually result in profound nervous system dysfunction in humans. Examples include neurodegeneration, microcephaly and brain tumors. Altered DNA repair signaling has been implicated in neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease. This implicates DNA repair proteins in genome maintenance in the nervous system. There are many different types of DNA damage and DNA repair. Each repair process has its own proteins and sequence of events that lead to either repair or cell death.

Ataxin-3 is known for its role in Spinocerebellar ataxia type 3 (SCA3), an autosomal dominant disorder caused by a repeat expansion in the ATXN3 gene. Symptoms are progressive and include prominent ataxia, impaired balance, spasticity and eye abnormalities. These symptoms are primarily a result of cerebellum dysfunction, but brainstem and spinal cord regions also show abnormalities in SCA3 patients. Recent studies have shown that ataxin-3 is part of a complex of proteins that repair single-strand DNA breaks. A crucial member of this complex, polynucleotide kinase 3’-phosphatase (PNKP), is actively involved in not only repairing single-strand but also double-strand breaks. Since the activity of PNKP is dependent on ataxin-3, this group of researchers were eager to investigate whether ataxin-3 also functioned in the repair of double-strand DNA damage.

Results of the RISCA study: gaining a better understanding of how ataxia symptoms first appear in at-risk patients

Written By Dr. David Bushart Edited by Celeste Suart

The RISCA study will help researchers design smarter, more efficient clinical trials by teaching us about the very early stages of SCA

Ataxia research has grown significantly in recent years. Although much work still remains, we are gaining a better understanding of how ataxia affects patients. Several exciting, new therapies are currently being studied. These advances would not be possible without the involvement of ataxia patients in clinical research studies. Some clinical studies are drug trials, where patients are enrolled to help researchers determine whether new therapies are effective at treating ataxia. However, other equally important types of clinical studies also exist. Ataxia patients play a critical role in the success of these studies.

What would an ideal treatment for ataxia look like? Ideally, we would be able to treat patients when their symptoms are very mild, or perhaps even before their symptoms appear at all. However, there are several obstacles to developing and testing this kind of hypothetical treatment:

First, it can be hard to know which patients to treat if symptoms are not yet present! There are many people who descend from patients affected by SCA of some kind. They have a 50% chance of being affected. While some of these people have been genetically tested, many have not. This makes it difficult to predict whether they will eventually develop SCA at all.

Second, along those lines, it could be very difficult to predict whether a drug is working to prevent symptoms from appearing if we don’t know precisely when symptoms should appear. It is much easier to tell if a drug is working when it is given to a patient with obvious symptoms – if their symptoms improve, the drug works.

Third, it can be difficult for researchers to enroll enough patients into clinical trials to get a meaningful result. This is complicated by the fact that we don’t know the answers to the first two questions above. Until recently, it remained unclear how a trial to test such a hypothetical treatment would need to be designed.

Thankfully, recent work has helped us better understand the answers to these questions. Results from the RISCA study were recently released. RISCA, which is a prospective, longitudinal, observational cohort study, was designed to study individuals who are at-risk for developing SCA, and how SCA symptoms might first appear.

Doctor and patient discussing something while sitting at the table — The RISCA study was designed to give doctors and patients more information about when ataxia symptoms first start to appear. This information is incredibly important for future ataxia clinical trials. Photo used under license by S_L/Shutterstock.com.

A promising biomarker to track disease progression in SCA3

Written by Dr. Ambika Tewari Edited by Dr. Gulin Oz

Neurofilament light chain could provide a reliable readout of how far an SCA3 patient’s disease has progressed

How often have you heard that the most effective way to treat a disorder is early intervention? In reality, “early” is not possible for many disorders because patients receive a diagnosis only after the appearance of symptoms. But what if there was a way we could tell that a patient will develop a disease – even before they have any symptoms? Thankfully, that’s exactly what researchers in the field of biomarkers are trying to do. Biomarkers are biological indicators that are not only present in patients before the manifestation of symptoms, but can also be used to measure disease progression. In the SCA field, there have been a recent series of articles that have shed light on a promising biomarker for SCA3.

Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph Disease, is the most common dominantly-inherited ataxia. It is caused by an expansion of CAG repeats (a small segment of DNA that codes for the amino acid glutamine) in the ATXN3 gene. An important feature of SCA3, as well as in other spinocerebellar ataxias, is the progressive development of symptoms. Symptoms usually occur across decades, and can be divided into three major phases: asymptomatic, preclinical, and symptomatic. In the asymptomatic phase, there is no evidence of clinical symptoms (even though the patient has had the SCA-causing mutation since birth). In the preclinical stage, patients show unspecified neurological symptoms such as muscle cramps and/or mild movement abnormalities. By the symptomatic (i.e., clinical) stage, patients have significant difficulty walking.

A Spinal Cord Motor Neuron sample stained purple. — Neurofilament light chain (NfL) is an important building block of neurons. But when neurons are damaged, NfL is released. Image of a spinal cord motor neuron courtesy of Berkshire Community College.

Currently in SCA research, disease progression is measured using the Scale for the Assessment and Rating of Ataxia (SARA). A score of 3 or more on the SARA differentiates clinical and preclinical groups. Structural and functional brain imaging methods (such as MRI) also track the progressive nature of the disease, like the SARA, but give us a visual picture of changes in the brain. Together, these methods have provided the SCA community with important insights into the clinical spectrum of each specific disease and its rate of progression. And, with the exciting progress we have recently made in the realm of SCA3 therapeutics, a biomarker that is cost-effective and easy to measure (like in a blood test) could provide a convenient way to assess how effective a potential treatment is.