Spotlight: The CMRR Ataxia Imaging Team

Location: University of Minnesota, MN, USA

Year Research Group Founded:  2008

What models and techniques do you use?

A photo of the CMRR Ataxia Imaging Team
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
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

Snapshot: What is RAN translation?

In many diseases caused by repeat expansion mutations in the DNA, harmful proteins containing repetitive stretches are found to build up in the brain. The repeat expansion mutation, when translated into a protein, results in an abnormally expanded repeat tract that can affect the function of the protein and have harmful consequences for the cells. Following a study published in 2011, we know that repeat expansion mutations can make additional harmful repeat-containing proteins by a process called Repeat Associated Non-AUG translation or RAN translation.

How are proteins made?

To get from DNA to protein, there are two main steps. The first step involves the conversion of a gene in the DNA into an instructional file called messenger RNA (mRNA). The second step is translation, this is where the cellular machinery responsible for making proteins uses mRNA as a template to make the protein encoded by the gene.

During translation mRNA is “read” in sets of three bases. Each set of three bases is called a codon and each codon codes for one amino acid. There is a specific codon that signals where to start making the protein, this codon is AUG. From the point where the cellular machinery “reads” the start codon, the mRNA is “read” one codon at a time and the matching amino acid is added onto the growing protein.

What happens when there is a repeat expansion mutation?

As the name suggests, Repeat Associated Non-AUG (RAN) translation is a protein translation mechanism that happens without a start codon. RAN translation occurs when the mRNA contains a repeat expansion that causes the mRNA to fold into RAN-promoting secondary structures. Because RAN translation starts without an AUG start codon, the mRNA can be “read” in different ways.

Let’s consider a CAG repeat expansion to illustrate this process. In the CAG “reading frame” a polyglutamine containing protein would be made because the codon CAG leads to incorporation of the amino acid glutamine. But a CAG repeat expansion could also be “read” as an AGC or a GCA repeat expansion if you don’t know where in the sequence to start “reading”. When “read” as AGC, the cellular machinery would incorporate the amino acid serine, making a polyserine repeat protein. In the GCA frame a polyalanine repeat protein would be made. This has been shown to happen in Huntington’s disease (HD). In HD, RAN-translated polyserine and polyalanine proteins accumulate in HD patients’ brains, along with the AUG-initiated mutant huntingtin protein containing a polyglutamine expansion.

Diagram show how different DNA sequences can be "read" and translated as different proteins
Overview of repeat proteins that can be produced by RAN-translation from a CAG expansion transcript. Designed by Mónica Bañez-Coronel.

To complicate matters more, RAN translation can happen from different repeat expansions, including those in regions of the DNA that aren’t normally made into proteins at all. Through the process of RAN translation, repeat expansion mutations in the DNA can give rise to multiple different proteins that aren’t made in healthy individuals. RAN proteins have now been identified in several neurodegenerative diseases where they have been shown to be toxic to cells, including in HD, spinocerebellar ataxia type 8, myotonic dystrophy type 1 and 2, and C9orf72 amyotrophic lateral sclerosis (ALS).

To learn more about the implications of RAN proteins for repeat expansion diseases see this article by Stanford Medicine News Center.

To learn more about the process of translation see this article by Nature.

https://www.nature.com/scitable/topicpage/translation-dna-to-mrna-to-protein-393/

For the original article describing RAN translation see this article by PNAS, and this article by Neuron about RAN translated proteins in Huntington’s disease.

Snapshot written by Dr. Hannah Shorrock and edited by Dr. Mónica Bañez-Coronel.