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Apr 10
2019

Research Byte: Altered location of ADAR2 in ALS

Research Bytes
Packard researchers at the Barrow Neurological Institute uncover a novel function of the C9orf72 mutation, delivering invaluable insight into the pathogenesis of ALS

Deoxyribonucleic acid, or DNA, is the unique-to-you genetic code found in all of the cells of your body. Humans have over 99% of the same DNA as one another, but the differences in our DNA contribute to what makes all humans look, act, and think differently.  Additionally, small changes or mutations in DNA can contribute to the development of diseases, such as ALS.  For example, one of the most common genetic causes of ALS involves a mutation in the gene C9orf72, but until recently the actual effects of this mutation were not very well understood.  A new study published in Acta Neuropathologica led by Packard Center investigator Associate Professor Dr. Rita Sattler of the Barrow Neurological Institute and conducted in collaboration with several Packard Center colleagues, however, uncovers a novel function of the C9orf72 mutation, delivering invaluable insight into the pathogenesis of ALS. 

The DNA in your cells is like an instruction manual, so in order for your genetic code to be converted into functioning parts of a cell, it first must be transcribed into RNA then translated into proteins.  These conversion processes are incredibly complex and littered with critical editing steps along the way.  One such enzyme that edits RNA is termed ADAR2.  The enzyme is critical for survival, as animals without ADAR2 die a very early death.  In normally functioning neurons ADAR2 is located in the nucleus, the control center of the cell where DNA is made into RNA. When Dr. Sattler and her team searched for ADAR2 in the nuclei of ALS-affected neurons, however, they found it instead in the main cytoplasm component of the cells.  Similar to how you wouldn’t be able to drive a car if the steering wheel was located in the trunk instead of the front seat, Sattler and her colleagues hypothesized that proper RNA editing couldn’t occur if ADAR2 is located in the cytoplasm instead of the nucleus.  

The team of researchers confirmed the mislocalization of ADAR2 using samples from both human with ALS and a mouse model of the disease.  Human tissues were obtained from Target ALS who, according to Dr. Sattler, “make an incredible effort to collect tissue from biobanks across the country and make them accessible to researchers who want to use them.” Sattler’s group also collaborated with researchers at Mayo Clinic Jacksonville to utilize an ALS mouse model with a similar C9orf72 mutation.  They found that overall levels of ADAR2 were normal but that the enzyme was in the incorrect spot, the cytoplasm, in all tissues studied. 

To examine the functional consequences of ADAR2 mislocalization, the scientists collaborated with researchers at the Translational Genomics Research Institute (TGen) in Phoenix and looked at known ADAR2-relevant RNA editing sites and compared editing levels in human tissue samples from C9orf72 ALS/FTD patients and non-ALS controls.  They found vast RNA editing abnormalities in C9orf72 ALS/FTD.  Future studies are required to determine how these RNA editing changes cause toxic effects in ALS, but the identification of pathways that are impacted already provide exciting leads.  In the last experiment, the researchers genetically modified cells that do not allow ADAR2 to go into the nucleus, mimicking the effects of the C9orf72 mutation in ALS.  The team observed similar errors in RNA editing, providing definitive proof that ADAR2 in the cytoplasm spells bad news for cellular function.

When asked about her laboratory’s future directions, Dr. Sattler mentions the first author of the paper, Stephen Moore.  “He is an incredibly talented graduate student in my lab who pushed the project when I was ready to quit,” Sattler states.  Because of his perseverance we have been, “catapulted … into a position where we have all of these thoughts and ideas.  Which one of these pathways could be otherwise targeted independent of trafficking? What are some other ways we can look further downstream? Maybe if we target downstream mechanisms we can delay disease progression.”  While Moore and the rest of Dr. Sattler’s team are motivated to examine ADAR2-related mechanisms and pathways in more detail, they are also extremely excited about their recently initiated studies using drugs that target the transport of proteins between the nucleus and cytoplasm.  The researchers hypothesize that by stopping ADAR2 from accumulating in the cytoplasm in ALS, normal RNA editing would occur as it does in healthy neurons.  Drugs with a similar mechanism are currently studied for advancement into ALS clinical trials, and Dr. Sattler plans to explore their therapeutic potential not just for ALS/FTD patients with the C9orf72 mutation, but also for sporadic ALS patients and individuals with other dementias. 

This project was a collaborative effort that included other Robert Packard Center investigators: Drs. Leonard Petrucelli, Veronique Belzil and Justin Ichida.

~Kristen Hollinger 

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