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New study shows circular RNA can encode for proteins

26/03/2017

Research shows RNA molecules until now considered "non-coding" can encode for proteins

Scientists in Israel and Germany have discovered a protein-encoding function for circular RNA, a kind of RNA molecule that is highly active in brain cells and could play an important role in neurodegenerative diseases.

Several years ago, scientists discovered a new type of RNA molecule. Unlike all other known RNAs, this molecule forms a closed loop, and was therefore labeled circular RNA (circRNAs). Although circRNA molecules are abundant - in particular in the brain where they accumulate as we age - little is known about their function. In contrast to messenger RNAs (mRNAs), which are generated from genes and have the information to make proteins, circRNAs were previously thought to perform other duties in the cells.

Now, in an article published in the prestigious journal Molecular Cell, Prof. Sebastian Kadener and colleagues at the Hebrew University of Jerusalem, in collaboration with researchers of the Berlin Institute for Medical Systems Biology (BIMSB) at the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) in Berlin, have demonstrated that circRNAs can encode for proteins.

This discovery reveals an unexplored layer of gene activity in a type of molecule not previously thought to produce proteins. It also reveals the existence of a new universe of proteins not yet characterized.

To determine whether circRNAs are translated, the researchers used Drosophila (fruit flies) and developed or adapted various techniques from molecular biology, computational biochemistry and neurobiology. They showed that specific circRNAs molecules are bound to ribosomes, the machinery that makes proteins, and they were able to find proteins produced from these molecules.

They also found that translated circRNAs are associated with specific places in the cells, in particular synapses, the junctions where electrical impulses pass from one nerve cell to another nerve or muscle cell. Indeed, the proteins produced from these circRNAs are present in synapses and are translated in response to specific signals, e.g. when the flies did not have access to food for 12 hours. This suggests that communication between neurons might involve unknown and uncharacterized mechanisms. Moreover, starvation and other pathways that induce the translation of circRNAs are also involved in aging, suggesting a strong link between circRNA translation and aging and a possible role for these molecules in neurodegenerative diseases.

As circRNAs are extremely stable, they potentially could be stored for a long time in compartments more distant to the cell’s body like axons of neuron cells. There, the RNA molecules could serve as a reservoir for proteins being produced at a given time.

According to Prof. Kadener, from the Biological Chemistry Department at the Hebrew University's Alexander Silberman Institute of Life Sciences, "By identifying the function of circRNAs, this research helps advance our understanding of molecular biology, and can be helpful in understanding aging or neurodegenerative diseases."

Prof. Nikolaus Rajewsky, of BIMSB/Max Delbrück Center for Molecular Medicine, added: “We think that translation of circRNAs is very interesting and that its prevalence and importance must be further investigated.”

Prof. Gil Ast, from the Department of Human Molecular Genetics & Biochemistry, at the Sackler Medical School at Tel Aviv University, who was not involved in the current study, said: "This study by Kadener and collaborators demonstrates that some circRNAs are translated. They show that the circRNAs translate mainly in the brain, likely in synapses. This is a very important, promising and timely discovery that gives an important hint of the function of these abundant yet uncharacterized RNAs. These findings are very important also due to the possible involvement of circRNAs in brain related diseases."

Among the circRNAs that Prof. Kadener showed to be translated is circMbl, which is generated from the muscleblind gene. Importantly, defects in muscleblind function are known to cause a severe degenerative disease called myotonic dystrophy. Characterized by progressive muscle wasting and weakness, this is the most common form of muscular dystrophy that begins in adulthood. Considered together, the role played by muscleblind in regulating circRNAs, combined with these molecules' abundance and translation in the brain, suggests that circRNAs might be involved in development of myotonic dystrophy.

Now, the researchers would like to explore how important circRNA translation is for normal brain function and whether circRNAs are involved in aging and age-related disorders. They would also like to analyze the mechanism of translation of circRNAs. This might teach us more generally about translation as a central process in the cell.

The research is published in Molecular Cell as “Translation of circRNAs”. Kadener’s group was supported by a Consolidator Grant from the European Research Council (ERC). The work was a collaborative effort between the Kadener group and several groups at the Max Delbrück Center for Molecular Medicine (MDC) in Berlin including the groups of Nikolaus Rajewsky, Marina Chekulaeva, Markus Landthaler and Gunnar Dittmar.

FUNDING: SK is funded by the ERC Consolidator Grant (ERC #647989). M.C., N.R. and L.R. are supported by the Einstein foundation grant “Single molecule RNA network”. ER was supported by the Berlin School of Integrative Oncology (GSC 1091). MJ received a fellowship from DFG (GRK#1772). CS is funded by BIF. N.R.P. is funded by a JBC fellowship. NR and CS is part of the SIGNGENE program between the MDC and HUJI.

CITATION: Pamudurti, Nagarjuna Reddy et al.: "Translation of circRNAs”. Molecular Cell, March 23, 2017. doi: 10.1016/j.molcel.2017.02.021.

PHOTO: http://media.huji.ac.il/new/photos/hu170223_circrna.jpg - Circular RNAs (circRNA) are produced in the cell nucleus after they are copied from the DNA and closed. This new research shows that some of them are translated and produce protein once they are exported from the nucleus.  (Image courtesy Sebastian Kadener)

New study shows circular RNA can encode for proteins
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Single Dose of Novel Peptide Protects Cognitive Function After Mild Traumatic Brain Injury (mTBI)

11/07/2016

New molecules, developed by Hebrew University of Jerusalem scientists, reduce inflammation, cell death and cognitive impairments following traumatic brain injury in mice

Whether at school, in car accidents, on the sports field or the battlefield, mild traumatic brain injury (mTBI) is a common part of our lives. It is especially frequent among children, athletes, and the elderly. Now, scientists at the Hebrew University of Jerusalem have shown that a single dose of a new molecule they developed can effectively protect the brain from inflammation, cell death, and cognitive impairments that often follow a mild traumatic brain injury.

Because it lacks visible external signs or objective structural brain damage, mTBI is an under-diagnosed injury. Yet it is often accompanied by long-lasting cognitive, behavioral and emotional difficulties associated with biochemical and cellular changes.  While most symptoms of mTBI are substantially resolved within days or weeks of the injury, up to 50% of mTBI patients experience symptoms at one-year post-injury. These can include psychological symptoms, subjective cognitive impairments, and somatic (physical) complaints.

These changes could result from an increase in glutamate levels, oxidative stress, opening of the blood-brain-barrier, and in particular inflammatory activity followed by cell death (apoptosis).  

Currently there is no effective treatment for patients with mTBI. 

“It is widely known that external or internal injury strongly activates the inflammatory response and leads to cell death (apoptosis) through the MAPK pathways, which are involved in the cellular responses that lead to inflammation in brain cells,” explains Prof. Daphne Atlas, from the Department of Biological Chemistry in the Alexander Silberman Institute of Life Sciences at the Hebrew University of Jerusalem. “Therefore, for reversing the effects of mTBI it is essential to calm the inflammatory pathways.”

At her laboratory in Jerusalem, Prof. Atlas has developed new molecules derived from the active site of Trx1, called thioredoxin-mimetic peptides (TXM-peptides). Thioredoxin (Trx1) is a major protein that maintains the oxidation/reduction state of the cells. In its reduced form it is bound to another protein (ASK1), which is released upon oxidation of Trx1 and activates a chain of enzymatic reactions that lead to inflammation. 

The newly-synthesized thioredoxin-mimetic peptides (TXM-peptides) have been shown to protect cells from early death via the activation of inflammatory pathways. Comprising 3 or 4 amino acids, these peptides have dual activity: they mimic the antioxidant activity of Trx1, and simultaneously inhibit the activity of enzymes called MAPK within the inflammatory pathway, preventing inflammation and cell death.

TXM-CB3 was previously shown to effectively lower MAPK activity in animal models of asthma and in the brain of rat model of diabetes [Kim et al 2011; Bachnoff et al 2011; Cohen-Kutner et al 2013, 2014]. The peptides managed to cross the blood-brain barrier and improve the condition of brain cells by lowering the inflammatory processes.

In the current study, published in the peer-reviewed journal PLOS ONE, Prof. Atlas and colleagues explored the impact of TXM-peptides, TXM-CB3 and TXM-CB13 (DY70; provided by OneDay Biotech and Pharma Ltd), on preventing mTBI cognitive secondary injury.  The experiments were performed in collaboration with researchers at Tel Aviv University, Prof. Chagi Pick and Dr. Renana Baratz-Goldstein

Researchers induced cognitive impairments in anesthetized mice by a weight drop resulting in mild traumatic brain injury. The mice showed a decrease in spatial memory in the Y-maze test and a loss in visual learning ability in the novel object recognition test.  Lower learning ability was also detected 30 days post injury in the mTBI mice.

In these two independent tests, a single dose of either one of the TXM-peptides administered 60 minutes post-injury, at a 50 mg per kg of body weight, significantly improved the decline in cognitive performance and learning ability at 7 and 30 days post injury. In addition, the two TXM-peptides were found highly effective at inhibiting the MAPK activity in neuronal cells grown in tissue culture.

“This research demonstrates the potential for TXM-peptides to significantly reduce cognitive impairment after mild traumatic brain injury,” said Prof. Atlas. “Further studies are required to establish and examine the potential of a single dose of TXM-peptide in preventing damage if administered even one hour after brain trauma in human scenarios — for example, in chronic traumatic encephalopathy observed in American football players, which result from multiple concussions and other types of blows to the head.

"Another advantage to using peptides is in significantly reducing the risk of causing toxic effects, because they consist of amino acids which are the natural building blocks comprising cell proteins, in contrast to the use of drugs that are not natural.  So TXM-CB3 and TXM-CB13 are promising treatment candidates to prevent secondary damage that affect brain function,” said Prof. Atlas.

About The Hebrew University of Jerusalem

The Hebrew University of Jerusalem is Israel’s leading university and premier research institution. Founded in 1918 by such innovative thinkers as Albert Einstein, Martin Buber and Sigmund Freud, the Hebrew University is a pluralistic institution where science and knowledge are advanced for the benefit of humankind. The Hebrew University is ranked internationally among the top 100 universities in the world, and first among Israeli universities. Serving 23,500 students from 85 countries, the Hebrew University produces a third of Israel’s civilian research, and its faculty are at the forefront of the international academic and scientific communities. For more information, please visit http://new.huji.ac.il/en.

FUNDING: This research was supported by the Ari and Regine Aprijaskis Fund at Tel-Aviv University, and by The H.L Lauterbach Fund (Hebrew University) to Daphne Atlas.

CITATION: Baratz-Goldstein, R., Deselms, H., Heim, L. R., Khomski, L., Hoffer, B. J., Atlas, D., & Pick, C. G. (2016). Thioredoxin-Mimetic-Peptides Protect Cognitive Function after Mild Traumatic Brain Injury (mTBI). PLoS ONE11(6), e0157064. http://doi.org/10.1371/journal.pone.0157064 (Link:  http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0157064)

Single Dose of Novel Peptide Protects Cognitive Function After Mild Traumatic Brain Injury (mTBI)
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