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RNA Translation and Motor Neuron Diseases

By Emily Zhou
June 2010

Paul Anderson, M.D., Ph.D.
"When eukaryotic cells are exposed to stress, one of the first things they do is to shut down general protein synthesis," Anderson told his NIEHS audience. "This helps to conserve anabolic energy so cells can divert their energy to repair stress-induced damage." (Photo courtesy of Paul Anderson and Harvard University)

"Because stress-induced reprogramming of  protein translation can help cells survive adverse environmental conditions,  secreted angiogenin may activate an 'infectious' stress response program that  allows stressed cells to warn their brethren of approaching noxious stimuli,"  explained Anderson. "This may occur at the organismal level by secretion of  angiogenin from the liver, or at the tissue level by secretion of angiogenin from  stressed cells within peripheral tissues."
"Because stress-induced reprogramming of protein translation can help cells survive adverse environmental conditions, secreted angiogenin may activate an 'infectious' stress response program that allows stressed cells to warn their brethren of approaching noxious stimuli," explained Anderson. "This may occur at the organismal level by secretion of angiogenin from the liver, or at the tissue level by secretion of angiogenin from stressed cells within peripheral tissues."    (Graphic courtesy of Paul Anderson)

In a May 10 talk at NIEHS, Paul Anderson, M.D., Ph.D., explored the delicate balance of protein translation, initiation, and repression. His seminar, titled "Polysomes, P-bodies and Stress Granules: Spatial Control of mRNA Translation/Decay," described how protein translation repression is an important process that enables cells to modulate protein expression.

Anderson(http://anderson.bwh.harvard.edu/01-Lab%20Members/1=Paul%20Anderson%20Page/PJA.html) Exit NIEHS is the K. Frank Austen Professor at the Harvard Medical School and the associate chief of the Division of Rheumatology, Immunology, and Allergy at the Brigham and Women's Hospital. He is recognized as an expert in post-transcriptional regulation of inflammatory cytokine production, translational initiation, and autoimmunity induced by environmental stressors. Both Anderson's research and clinical work have advanced understanding of how RNA translation contributes to human disease pathologies. One of the exciting projects in his laboratory demonstrated the role of RNA translational repression in promoting motor neuron survival.

Balance of translation initiation and repression

Anderson explained that protein translation in eukaryotic cells is delicately balanced by two opposing forces -- translation initiation and translational silencing. Messenger RNA (mRNA) ready for protein synthesis is capped with 7 methyl guanine (7mG) at the 5' end and occupied by a complex of initiation factors. This complex scans mRNA until it reaches the adenine-uridine-guanine (AUG) start codon, then releases initiation factors and binds ribosomes to allow protein translation. This process is balanced by translational silencing that involves a class of protein repressors to attenuate protein synthesis.

According to Anderson, translational silencing is constitutive in cells but can be aggravated under stress conditions, such as heat, oxidative stress, UV irradiation, and hypoxia. T-cell-restricted intracellular antigen-1 (TIA-1) protein, one of the translation repressors, assembles the untranslated RNA into stress granules (SGs), which consist of stalled translation complexes. Anderson has used immunofluorescent microscopy  to demonstrate the formation of stress granules through arsenite insult in the cell cytoplasm.

Complex composition of stress granules

Anderson argues that cells contain what he calls "mRNA triage" units that sort RNA between sites of translation initiation and sites of translation silencing. SGs determine RNA fate by selecting to degrade RNA, store RNA, or re-initiate translation.

SGs are composed of many different proteins that have functions in cell metabolism as well as cell survival. Anderson has identified genes required for the assembly of SGs using a genomic small interfering RNA (siRNA) screen. He also discovered over 100 genes affected SG formation when knocked down, and most of these genes are involved in translation and protein signaling pathways. One such gene is RACK1. When expressed, RACK1 is sequestered at SG where it inhibits stress-induced apoptosis.

TiRNA, angiogenin, and motor neuron disease

Anderson's laboratory has recently discovered that a class of stress-induced small RNAs (tiRNA), natural products of cells, promotes translational repression. TiRNAs, which are 30 or 40 nucleotides in length, are formed through selective cleavage of transfer RNA (tRNA) by angiogenin -- a 14 kilo Dalton (kDa) RNAse that is secreted in response to hypoxia.

Angiogenin promotes motor neuron survival, and mutants of angiogenin are associated with the neural degenerative disease Amyotrophic Lateral Sclerosis (ALS). Anderson noted that a point mutation in the angiogenin gene reduces its ability to cleave tRNA and produce tiRNA. Both angiogenin and tiRNA are important in translation repression in cells exposed to environmental stresses. However, the mechanism by which tiRNAs inhibit protein synthesis is still under investigation.

Hosted by NIEHS Mammalian Aging Group Postdoctoral Fellow Thaddeus Schug, Ph.D., Anderson's seminar was the most recent talk in the NIEHS Laboratory of Signal Transduction Seminar Series.

(Yixing [Emily] Zhou, Ph.D., is a postdoctoral research fellow in the NIEHS Laboratory of Signal Transduction.)



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