New misfolding mechanism spotted

Scientists appear to have discovered a new general mechanism for generating misfolding proteins, perhaps underlying some cases of neurodegeneration, according to a new online report in Nature.When it comes to diseases involving misfolded proteins, scientists typically link a particular disorder with a specific misfolded protein, such as a prion or beta-amyloid, said coauthor Susan Ackerman at the Jackson Laboratory in Bar Harbor, Maine. This study, in contrast, found a more generalized mechanism that upsets the accuracy of RNA translation, creating misfolded proteins."Here we're talking about a mechanism that's responsible for many, many different proteins misfolding," she told The Scientist. "This is the first example of this mechanism at the mammalian level, and I doubt it's the only one."Ackerman and her colleagues focused on the sticky mutation in mice, which leads to tremors and ataxia due to loss of Purkinje cells in the cerebellum. The researchers found many signs mutant cells were accumulating misfolded proteins. For instance, immunofluorescence analysis showed numerous clumps throughout the cytoplasm and nucleolus loaded with proteins marked for destruction with ubiquitin.Genome scans isolated the sticky mutation, and sequencing of complementary DNA revealed a missense mutation in a tRNA synthetase gene. During protein synthesis, tRNAs carry amino acids to growing peptide chains at ribosomes. This particular gene, alanyl-tRNA synthetase, loads or "charges" tRNA with alanine, which the tRNA helps incorporate into proteins. The sti mutation lies in the gene's editing domain, which ensures the enzyme does not add the wrong amino acid to tRNAs, such as serine or glycine, which resemble alanine in size.To determine whether mutant cells were incorporating amino acids other than alanine into proteins, which might explain the apparent misfolding, Ackerman and her colleagues raised normal and mutant mouse embryonic fibroblasts in culture with high concentrations of various amino acids. They found cultures rich in serine increased mutant cell death dramatically in a dose-dependent manner. Glycine had similar, but less pronounced, results. And relative to normal enzymes, mutant forms produced significantly higher levels of serine-loaded tRNAs. "Presumably any protein with alanine can get misfolded in these mutants," Ackerman said. Future experiments should scan other diseases for mutant tRNA synthetases, Karl Herrup at Rutgers University in New Brunswick, N.J., who did not participate in this study, told The Scientist. "This could be a tip of a huge iceberg, not just in humans, but in livestock, plants, everything. These enzymes are as old as the hills, if not older."Now that many experiments are conducted using expression arrays, "this kind of effect is going to fly under the radar," Herrup added. "It emphasizes the need for a systems approach, and is a strong mandate for taking proteomics seriously.""These findings are going to force us to think more carefully about how much error protein synthesis living systems can tolerate before you have some consequences," Christopher Francklyn at the University of Vermont in Burlington, also not a co-author, told The Scientist."One might explore in a mouse model what happens when you basically make protein synthesis less accurate in different cells or tissues," Francklyn added.Some scientists may question why this happens in Purkinje cells, and not other neurons, Ackerman said. "One possibility is that Purkinje cells in mice are inherently less able to degrade misfolded proteins." This would then suggest that as misfolded protein levels increase, other neurons would start dying as well, she explained -- something she said she and her colleagues plan to investigate further.Charles Choi cchoi@the-scientist.comLinks within this article:J.W. Lee et al. "Editing-defective tRNA synthetase causes protein misfolding and neurodegeneration." Nature, August 13, 2006. http://www.nature.comM. Fogarty. "Prions - The terminators." The Scientist, July 28, 2003. http://www.the-scientist.com/article/display/13974/M.W. Anderson. "Amending the amyloid hypothesis." The Scientist, October 25, 2004. http://www.the-scientist.com/article/display/15006/Susan Ackerman http://www.jax.org/staff/susan_ackerman.htmlS. Bunk. "Ataxia discoveries open window to neurodegeneration." The Scientist, April 26, 1999. http://www.the-scientist.com/article/display/18517/A. Constans. "Another chapter in going from blood to brain." The Scientist, November 7, 2005. http://www.the-scientist.com/article/display/15822/J. Hall et al. "Mining the ubiquitin pathway." The Scientist, December 5, 2005. http://www.the-scientist.com/article/display/15911/Christopher Francklyn http://biochem.uvm.edu/faculty_details.php?people_id=68

New misfolding mechanism spotted

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