Methylation Links Addiction To Stress and Depression

Depression and substance abuse also go together like a horse and carriage: Each increases the risk for the other. Throw in stress and you've got the ménage a trois from hell. Now, scientists from the Mount Sinai School of Medicine have worked out one reason why substance abuse makes people more vulnerable to stress-related illnesses. In mice, repeated cocaine use changed the methylation patterns of brain cells, which in turn made the animals more vulnerable to developing depression-like behaviors in response to social stress. Knocking out the enzyme that controlled the specific methylation patterns that were associated with substance abuse made the animals even more vulnerable to stress, while increasing its activity made them more resilient. The authors noted that "identifying such common regulatory mechanisms may aid in the development of new therapies for addiction and depression." Their findings appeared in the Aug. 25, 2011, issue of Neuron.

What Unites ALS

Scientists from Northwestern University's Feinberg School of Medicine identified a mutation that is present in the majority of patients with amyotrophic lateral sclerosis, or ALS, also known as Lou Gehrig's disease. Their study identified a common underlying cause for familial, sporadic and brain-targeting forms of the disease, and one that could be targeted therapeutically. The authors found that 70 percent of ALS patients have mutations in the ubiquilin gene, a part of the ubiquitination system that tags proteins for breakdown and recycling. It appears that when this gene does not function properly, proteins accumulate and ultimately impair neural functioning. The authors contended their findings may show new ways to fight not just ALS, but other neurodegenerative disorders as well; many neurodegenerative disorders are characterized by protein accumulations such as beta-amyloid plaque in Alzheimer's disease, Lewy bodies in Parkinson's disease, and others. The work appeared in the Aug. 21, 2011, advance online edition of Nature.

Tricking Clostridium Difficile

Scientists from the University of Texas Medical Branch have discovered how intestinal cells defend themselves against the toxins produced by C. difficile, a bacterium that is among the most frequent hospital-acquired infections. Roughly 1 percent of patients will acquire a C. difficile infection during a hospital stay. The infection can cause gut problems that range from disgusting to life-threatening. C. difficile becomes virulent only after it cleaves itself with a protease, which in turn is activated when the bacterium senses high levels of the intracellular signaling molecule InsP6. But cells, too, can sense the presence of the bacterium, and protect themselves by preventing the protease from being activated. The authors also found they were able to lessen the symptoms of C. difficile infection in mice by treating them with InsP6; high levels in InsP6 in the animals' bloodstream essentially tricked the C. difficile toxin into cleaving itself before it had entered cells. The work appeared in the Aug. 21, 2011, issue of Nature Medicine.

Exploring Ebola's Entry

Two independent teams of researchers, a Dutch-American team led by the University of Amsterdam and a Harvard-led team, reported new insights on how filoviruses – including the much-feared Ebola – infect cells. To date, Ebola outbreaks have been limited in scope, but the virus's fatality rate of 75 percent, spectacular symptoms and status as the star of the thriller "Outbreak" have caused what the authors of one of the studies called "a high level of public concern" about the virus. Both teams found that the cholesterol transporter Niemann-Pick C1 is essential for viruses to gain entry into cells. Mutations in the Niemann-Pick gene lead to Niemann-Pick disease, a severe metabolic disorder, and the authors of one study suggested "the unanticipated role for the hereditary disease gene NPC1 in viral entry, infection and pathogenesis may facilitate the development of antifilovirus therapeutics." The papers appeared in the Aug. 25, 2011, issue of Nature.

Mediator Complex Mutations Cause Fibroids

Researchers from the Finnish University of Helsinki have used exome sequencing to identify a mutation that is present in more than two-thirds of fibroids. Uterine leiomyomas, or fibroids, are benign tumors, but only in the sense that they do not metastasize; they affect more than half of all women older than 45 and can cause pain and bleeding. In younger women they are less frequent but more problematic, often causing infertility. In their study, the authors sequenced the exomes of 18 fibroid tumors and found that the majority of them had mutations in the same gene, the mediator complex subunit12, or MED12 gene. Confirming their findings in 200 more samples, they found MED12 mutations in 70 percent of them. All mutations were in the same exon of the protein. The work is a step toward understanding how fibroids arise and may point to MED12 as a therapeutic target to treat them. It was published in the Aug. 25, 2011, online edition of Science.

. . . And Intellectual Disability

Another study published last week, this one by French researchers from the University of Strasbourg and the INSERM Institute, linked another subunit of the mediator complex to intellectual disability. Mediator is a multiprotein complex that regulates gene expression, and the authors contended that "reports linking Mediator subunits to human diseases may . . . allow a deeper understanding of how cell-specific expression programs are regulated." The authors first sequenced a large family and found that intellectual disability was present in those members of the family who had a mutation in MED23. The mutation affected the expression of immediate-early genes, or genes whose expression levels change very rapidly in response to cell stimuli. Some immediate-early genes play roles in learning and memory. The authors looked at patients with other neurological disorders and also found that immediate-early genes tended to be defective. Based on their results, the authors "propose that altered [immediate-early gene] expression might provide a molecular signature for cognitive deficits." Their work appeared in the in the Aug. 26, 2011, issue of Science.

PARP Inhibitors Branch Out

Poly(ADP-ribose) polymerase or PARP inhibitors are in clinical development for the treatment of cancers that cannot repair double-stranded DNA breaks, such as those that lack BRCA. But scientists from the Canadian BC Cancer Agency have tested the PARP inhibitor olaparib (AstraZeneca plc) in women without BRCA mutations, and found that their response rate, though lower than the 41 percent response rate of women with BRCA mutations, was a still-respectable 24 percent. The authors treated 64 patients with recurrent or recurrent high-grade serous or poorly differentiated ovarian carcinoma in a Phase II, multicenter, open-label, nonrandomized study. Twenty-six women with triple-negative breast cancer also were treated, but no objective responses were seen in that indication. The authors concluded that "olaparib is a promising treatment for women with ovarian cancer and further assessment of the drug in clinical trials is needed." Their results appeared in the Aug. 22, 2011, early online edition of Lancet Oncology.

New Axis of Appetite Identified

While studying the role of the tumor suppressor guanylyl cyclase, researchers at Thomas Jefferson University discovered that the hormone receptor plays a role in regulating food intake as well. Intestinal cells are important for controlling food intake through sensing nutrients in the gut, and the new studies showed that one way they do so is by secreting hormones that activate GCC into the circulation. Those hormones activate GCC in the brain, which suppress appetite. GCC knockout mice ate more than their wild-type counterparts; they were heavier than wild-type mice by about 10 weeks of age, and ultimately developed symptoms of metabolic syndrome, including insulin resistance and fatty livers. GCC was known to regulate eating in invertebrates, but the work is the first showing that it plays the same role in vertebrates. The findings appeared in the Aug. 25, 2011, issue of the Journal of Clinical Investigation.

Giving Tumors Measles Could Hasten Demise

Researchers at the Canadian Dalhousie University discovered that the tumor cell marker Nectin 4, or PVRL4, is a receptor for measles virus, suggesting the possible use of measles virus to help fight cancer. Several companies, as well as academic research groups, are testing oncolytic viruses in the clinic, and measles viruses are in clinical trials for brain, ovarian and pancreatic cancer; the new findings suggested the approach may be more widely applicable to different tumor types, including lung, breast, colon and ovarian cancers. The authors noted there are "anecdotal reports in the literature where natural MV infections were shown to reverse cases of Burkitt's lymphoma and Hodgkin's disease. . . . One can presume that [wild-type measles virus] infected the tumors and triggered immune attack against them." The findings appeared online in PLoS Pathogens on Aug. 25.

Anti-inflammatory Cytokine Protects Against IBD

Interleukins are most often pro-inflammatory. But scientists from the University of California, San Diego School of Medicine, and the University of Colorado identified a new member of the interleukin family, IL-37, that is anti-inflammatory and appears to protect against inflammatory bowel disease. The authors engineered mice to express human IL-37 and then induced colitis in the animals. The transgene was expressed only after the mice had damage to their intestines; when it was expressed, it protected mice from damage to their bowels, reducing both clinical symptoms and cell damage. How the cytokine protects the intestinal lining is not yet clear, but the authors concluded that IL-37 is a "key modulator of intestinal inflammation." Their work appeared in the Aug. 22, 2011, online issue of the Proceedings of the National Academy of Sciences.

– Anette Breindl, Science Editor