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Jul 12
2019

Research Bit: Unconventional translation of nucleotide repeats

Research Bits
The Packard Center welcomed Peter Todd from the University of Michigan to a recent Investigator's Meeting.

Meeting Date: 12 July 2019

Presenter: Peter Todd, MD, PhD

Talk Title: Unconventional translation of nucleotide repeats

What was the question being asked?

Dr. Todd’s laboratory is interested in studying the roles of RNA in various neurodegenerative disorders. In order for a gene to be made into a protein, a process called translation, the DNA which makes up that gene is first made into a chemical intermediary, called RNA (ribonucleic acid), in a process called transcription. One of the most common disease genes for ALS, called Chromosome 9openreading frame 72(C9orf72), involves a hexanucleotide repeat expansion in an intron (a normally un-translated region) of the gene. In C9-ALS, there is translation of the C9 RNA containing this repeat region, and Dr. Todd’s research is focused on what causes this unconventional translation to occur. They then try to manipulate this process using cell culture systems and mouse models, and ultimately use these systems to discover drugs which may modify this process. 

Why is this important for ALS research?

While it’s not clear exactly how the C9orf72 repeat expansion leads to ALS, one idea is that the mutation leads to pathological changes in the RNA structure, which leads to the production of unusually translated proteins that have toxic properties for cells. Interestingly, other repeat expansion diseases, such as Fragile-X Tremor-Associated Syndrome (FXTAS), also involve non-canonically translated proteins; therefore, the mechanisms behind this process in ALS might be similar to other neurodegenerative disorders where this occurs, and vice versa. Insights into one disease process might shed light on another.

What was the take-home message?

It appears that similar pathways and proteins are underlying non-canonical translation and toxic protein production in C9-ALS and FXTAS, one example being cellular stress. The overlap between these groups is not perfect though, suggesting there are similar but unique processes leading to non-canonical translation in each disease. 

How do you think the results of this study might impact future approaches to the treatment of ALS? 

Dr. Todd’s group has begun screening drugs that inhibit this abnormal translation process; however, many of these drugs were found to be toxic to neurons grown in the lab when used at the concentrations needed to be effective. So, while these exact compounds may not be useful for therapies, studying the way these classes of drug inhibit abnormal translation may lead researchers to discover better, more precise drugs that can be clinically useful.

 

Jenna C. Glatzer
PhD Candidate, Cellular and Molecular Medicine Graduate Program
Laboratories of Dwight Bergles and Jeff Rothstein 
Johns Hopkins University School of Medicine 

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