From the journals

Published December 01 2017

We offer a selection of recent papers on a variety of topics from the Journal of Biological Chemistry, the Journal of Lipid Research, and Molecular & Cellular Proteomics.

This is your brain’s beta-synuclein on acid

The main component of pathological protein fibrils in Parkinson’s disease is alpha-synuclein. A closely related protein, beta-synuclein, typically does not form fibrils in the cytoplasm but appears to be involved in lysosomal dysfunction in some forms of dementia. In a paper in the Journal of Biological Chemistry, Gina Moriarty and colleagues at Rutgers University show that beta-synuclein forms fibrils at mildly acidic pH, suggesting that pH conditions in cellular microenvironments may contribute to beta-synuclein’s role in neurodegenerative diseases.

Biofilm disrupters in the human gut

The cholera-causing bacterium Vibrio cholerae occupies several niches, including living freely in water, colonizing crustaceans or invading the human intestine. Various environmental factors can induce or inhibit V. cholerae biofilm formation through a c-di-GMP signaling pathway. In a study in the Journal of Biological Chemistry, Richard Sobe and colleagues at Appalachian State University identify a polyamine called spermine that, at the concentrations typically present in the human gut, prevented V. cholerae biofilm formation. Thus, spermine may be an environmental signal that induces the pathogen to grow planktonically in the intestine, a state in which it can produce virulence factors.

Combo shows promise for treating lipid disorder

Patients with familial dysbetalipoproteinemia, or FD, have elevated cholesterol and triglycerides. The buildup of large lipoproteins can manifest in yellowish or orangey fat deposits under the skin of the palms, elbows, knees, feet and eyelids. The disease, caused by a defect in the gene apolipoprotein E, leads to premature hardening of the arteries, formally known as atherosclerosis. Patients usually need to adjust their diets and lifestyles and take cholesterol-lowering statins, but even then they may remain at increased risk of heart disease. Researchers at the University Medical Center Utrecht recently reported in the Journal of Lipid Research that adding a fibric acid derivative to lipid-lowering regimens seems to be beneficial for these patients. Fibrates have been known to reduce very low-density cholesterol and speed the removal of triglycerides from the blood. The team, led by Frank L.J. Visseren, conducted a randomized, placebo-controlled, double-blind study of 15 patients. “(T)he addition of bezafibrate to standard lipid-lowering therapy resulted in lower fasting and post-fat-load plasma lipids, which may significantly affect atherogenesis in FD (patients),” the authors wrote. “Combination therapy of statin/fibrate could be considered as standard lipid-lowering treatment in FD patients.” Bezafibrate, marketed under the brand name Bezalip and others, is an agonist of the dietary lipid sensors called peroxisome proliferator-activated receptors, or PPARs.

Why don’t long-lived whales develop cataracts?

The external eye anatomy of the bowhead whale shows a small palpebral fissure and thick and fleshy palpebra with a thick overlaying epidermis that protects the whales’ eyes from the extreme arctic environmental conditions, allowing them to maintain vision throughout their long lives.courtesy of North Slope Borough, Department of Wildlife Management, Utqiagvik, Alaska

In America, more than half of people age 80 and older have or have had cataracts. Other species also experience the lens clouding, which can cause blindness. Dogs, for example, typically live a decade or more and develop cataracts around age 6. (That’s around 42 in dog years.) Rats live a few years on average in labs and develop cataracts around age 2. Interestingly, bowhead whales are believed to live up to 200 years, which puts them among the longest-living mammals, and yet they do not develop cataracts. Researchers recently set out to study the whales’ specially adapted eyes to figure out why that might be the case. The research team, led by Douglas Borchman of the University of Louisville, collaborated with the Alaska Department of Wildlife Management. The department has a decades-long relationship with Eskimo whaling captains authorized by the International Whaling Commission to conduct subsistence hunts twice annually. Over the years, great numbers of whale eyes have been preserved for study. And what did all those eyeballs reveal? “We found that whale lenses have one of the highest sphingolipid contents of lenses from the species studied,” the authors reported in the Journal of Lipid Research. “Lens membranes with a high content of saturated sphingolipids … are less susceptible to oxidation because there is relatively less oxygen in these ordered bilayers, as well as fewer double bonds to become oxidized … (W)hale lens lipid composition and structure support the finding that lens lipid hydrocarbon order is directly related to the sphingolipid content and indirectly related to the phosphatidylcholine content of the lenses of many animals.” The authors said the strong correlation between sphingolipid composition and animal lifespan is worthy of additional study.

Why HIV combo therapies don’t work as expected

Second-line anti-HIV drugs include co-receptor antagonists and fusion inhibitors, which prevent viral entry into cells via different mechanisms. These drug classes are expected to act synergistically, but in practice sometimes they do not. In the Journal of Biological Chemistry, Koree Ahn and Michael Root of Thomas Jefferson University report that the strength of synergy between co-receptor antagonists and fusion inhibitors depends on co-receptor density and drug-target binding affinity. These results clarify steps in the HIV fusion process and suggest factors to consider when developing combination therapies.

A regulatory protein that aggregates in brain cancer

Gliomas are deadly brain cancers whose progression is strongly associated with overexpression of the RNA-binding regulatory protein HuR. Using clinical brain tumor samples, Natalia Filippova and colleagues at the University of Alabama show in a paper in the Journal of Biological Chemistry that increasing tumor severity was associated with increased multimerization and aggregation of HuR. They also identified the domains involved in multimerization, suggesting drug targets for slowing tumor progression.

Characterizing plant hormones

Plants secrete a diverse set of peptides that play crucial roles as signaling molecules to influence growth and development. However, many of these plant hormones have not been characterized. Investigators at Australian National University led by Michael Djordevic developed a mass spectrometry and bioinformatics strategy to identify the secreted peptidome from the roots and xylem sap of Medicago truncatula, a model plant organism for legume biology. They identified 759 spectra corresponding to 12 peptide hormones with different post-translational modifications. The modifications were shown to be important in the signaling roles of the peptides as demonstrated by the ability of hydroxylation at key positions in CEP peptides to elevate root nodule number. The study was published in Molecular & Cellular Proteomics.

This is a shoot of a 4-week-old Medicago truncatula, also called barrel clover, a small annual legume. courtesy of Ninjatacoshell, Wikimedia Commons

The sleeping sickness pathogen complex

The protozoan parasite Trypanosoma brucei is a pathogen that causes sleeping sickness, with an estimated 20,000 case per year. Although the genomic sequence of T. brucei has been reported, many of the predicted proteins lack classifiable homology to known proteins in other organisms, hindering efforts to understand its biology and discover potential therapies. In a study published in Molecular & Cellular Proteomics, investigators at the University of Dundee led by Michael Ferguson performed a protein correlation profiling approach using mass spectrometry to identify protein complexes from T. brucei. They identified and quantified profiles for 6,004 protein groups, from which 234 protein complexes were predicted. The data generated from the study were incorporated in an accessible online database as a resource for trypanosome biologists.

Vitamin D activation beyond the kidneys

Vitamin D is converted into its active form primarily in the kidneys in an endocrine-regulated process, but a small amount of vitamin D activation occurs in nonrenal cells and is regulated by inflammation. Understanding vitamin D biology has been hampered by the inability to disentangle endocrine and inflammatory regulation in vivo. In a paper in the Journal of Biological Chemistry, Mark Meyer and colleagues at the University of Wisconsin describe how they discovered a kidney-specific enhancer of vitamin D activation that specifically affects skeleton formation, paving the way for future studies.

Serpin mechanisms in blood disorder patients

Antithrombin deficiency is a rare blood disorder that greatly increases the risk for life-threatening blood clots. Many individuals with antithrombin deficiency have mutations affecting antithrombin’s reactive center loop, which inserts into thrombin’s active site to inhibit it. In the Journal of Biological Chemistry, Sonia Aguila and colleagues at the Universidad de Murcia describe how they identified an additional set of antithrombin deficiency–associated mutations in the distal region of antithrombins and showed that this domain is essential for the final steps of thrombin inhibition.

The antibody repertoire of colorectal cancer

The immunoglobulin genes that code for antibodies are highly rearranged in the genome, causing missed identifications of antibodies in mass spectrometry searches. A team led by Vineet Bafna at the University of California–San Diego developed a novel proteogenomic approach to identify the highly variable antibody peptides by developing a customized antibody database construction method. The tool, called AbScan, was used to create an antibody database from colorectal tumor samples using RNA-seq data, which then was used to search the mass spectrometry data. The study, reported in Molecular & Cellular Proteomics, identified 1,940 distinct antibody peptides in colorectal cancer. AbScan is freely available and can be used for understanding the immune response in other cancers.

Sasha Mushegian Sasha Mushegian is scientific communicator for JBC.

Angela Hopp Angela Hopp is executive editor of ASBMB Today and communications director for the ASBMB.

Saddiq Zahari Saddiq Zahari is a postdoctoral scholar at the University of California, San Francisco, and the editor for manuscript integrity at MCP.