Letters in 2012

Spinal and bulbar muscular atrophy (SBMA) is a neurodegenerative disease caused by aggregation of the androgen receptor (AR) protein. Here Gen Sobue and colleagues show that upregulation of miR-196a can reduce expression of AR mRNA and ameliorate disease symptoms in mouse models of SBMA.

Kaposi's sarcoma–associated herpesvirus (KSHV) can infect endothelial cells, leading to the development of Kaposi's sarcoma in some individuals. The mechanisms underlying cell entry by KSHV are not fully elucidated. ahn et al. now report that ephrin receptor tyrosine kinase A2 (EphA2) acts as a cellular receptor for KSHV and show that blocking EphA2 inhibits infection of endothelial cells.

Tony Lam and his colleagues show that the middle intestine senses glucose and has a role in a gut-brain-liver axis to regulate hepatic glucose production. They also show that an experimental form of bariatric surgery quickly ameliorates hyperglycemia in two rat models of type 1 diabetes, and the intestinal sensing of glucose they have identified probably contributes to this metabolic effect.

Entamoeba histolytica causes human amebiasis. Although antibiotic therapy for this infection exists, there are limited treatment options for this potentially fatal invasive disease. Anjan Debnath and colleagues now report their identification of auranofin, an approved treatment for rheumatoid arthritis, as a candidate new drug for combating E. histolytica infection.

High concentrations of some types of plasma lipoproteins, such as low-density lipoprotein, promote atherosclerosis and a wide range of vascular-related diseases. These pathogenic lipoproteins have in common the protein component apolipoprotein B. Through study of the effects of modulating lipoprotein levels in experiments involving zebrafish, mice and cultured human endothelial cells, Inbal Avraham-Davidi et al. uncover a potentially deleterious role of apolipoprotein B–containing lipoproteins as direct inhibitors of the angiogenic behavior of vascular endothelial cells.

The adipocyte-derived hormone leptin acts on the brain to signal the long-term status of energy balance in the body. Martin Myers and his colleagues narrow down the population of neurons in the brain that actuate leptin's effects on food intake, and thus systemic energy balance, to a relatively small percentage of Nos1⁺ cells in the hypothalamus.

A mobile genetic element—sasX—has a key role in the pathogenesis of methicillin-resistant Staphylococcus aureus (MRSA) infection. This rapidly spreading determinant of MRSA pathogenic success markedly enhances nasal colonization, lung disease and immune evasion.

Individual variation in pain sensation makes pain clinical trials quite challenging to interpret. Now, Michael Salter and colleagues report that genetic variation in the P2RX7 gene affects pore formation of the protein and pain sensation in humans.

Enteric neuron death is linked to the pathogenesis of inflammatory bowel disease. Now, Brian Gulbransen and his colleagues demonstrate that P2X7 receptor–pannexin-1 signaling is responsible for enteric neuron death in mouse models of colitis.

Dysregulated hepatic glucose production (HGP) is a key feature of type 2 diabetes (T2D). Masato Kasuga and his colleagues now show that under physiological conditions, the expression and activity of the protein CITED2 in the liver is altered in response to hormonal cues that regulate HGP. They also show in a mouse model of T2D that hepatic CITED2 expression is elevated and that its genetic knockdown reduces serum glucose concentrations, suggesting this protein as a possible therapeutic target in the clinic.

Drugs that induce redifferentiation of cancer cells are efficient only in some subtypes of AML. The authors show that sensitivity to pro-differentiation drugs such as ATRA can be induced by co-treatment with epigenetic drugs. An inhibitor of histone demethylase, LSD1, safely used as an antidepressant in humans, reprograms AML cells and makes them sensitive to the effects of ATRA in vitro and in vivo, suggesting that epigenetic interventions can increase response to cancer treatments.

Vitamin E has long been proposed to favor bone growth owing to its antioxidant properties. This study shows instead that, by promoting osteoclast fusion, vitamin E decreases bone mass.

The authors apply reverse engineering of transcriptional networks to identify the main functional drivers of the pro-leukemic transcriptional activity of TLX1 and TLX3, transcription factors usually altered in T-ALL. The network analysis uncovers RUNX1 as a key mediator of the effects of TLX factors and, consistently, mutations in RUNX1 are found in human T-ALL.

IgA antibodies directed against tissue transglutaminase 2 (TG2) are used as a serological marker of celiac disease. Ludvig M. Sollid and his colleagues provide an unbiased and thorough characterization of the mucosal antibody response directly from the effector compartment. They report that TG2-specific plasma cells are expanded in the duodenal mucosa of individuals with celiac disease. Antibodies cloned from these cells are of high affinity, show a restricted repertoire and minimal somatic hypermutation, and do not inhibit TG2 enzymatic activity.

Antiretroviral drug combinations for the treatment of HIV-1 infection have been determined on the basis of clinical trial outcomes, but without clear insight into why certain combinations are superior to others. Robert Siliciano and his colleagues present a quantitative basis for determining efficacious antiretroviral drug combinations.

Neuromuscular disease is often marked by insufficient neural activation of muscle activity, resulting in muscle weakness. Fady Malik and colleagues have developed an orally available small molecule that sensitizes muscles to neural activity by reducing the off rate of calcium binding to troponin C. They validate the therapeutic potential of this drug in vivo in a rat model of myasthenia gravis and show that treatment improves grip strength by 50%.

T cell acute lymphoblastic leukemia (T-ALL) is an immature hematopoietic malignancy driven mainly by oncogenic activation of NOTCH1 signaling¹. In this study we report the presence of loss-of-function mutations and deletions of the EZH2 and SUZ12 genes, which encode crucial components of the Polycomb repressive complex 2 (PRC2)^2,3, in 25% of T-ALLs. To further study the role of PRC2 in T-ALL, we used NOTCH1-dependent mouse models of the disease, as well as human T-ALL samples, and combined locus-specific and global analysis of NOTCH1-driven epigenetic changes. These studies demonstrated that activation of NOTCH1 specifically induces loss of the repressive mark Lys27 trimethylation of histone 3 (H3K27me3)⁴ by antagonizing the activity of PRC2. These studies suggest a tumor suppressor role for PRC2 in human leukemia and suggest a hitherto unrecognized dynamic interplay between oncogenic NOTCH1 and PRC2 function for the regulation of gene expression and cell transformation.

Tau aggregation is associated with neurodegenerative diseases called tauopathies. Ashley Bush and colleagues now report that aged tau-deficient mice develop motor and cognitive dysfunction that is linked to elevated iron levels in the brains of the mice.

Using mice with an amino substitution in the kinase PKG, a key regulator of blood vessel tone, Oleksandra Prysyazhna et al. provide evidence for the physiological importance of PKG oxidation and disulfide formation in maintaining normal blood pressure. These results clarify the nature of an enigmatic vasodilatory activity termed endothelium-derived hyperpolarizing factor and suggest that vascular oxidative stress can have blood pressure-lowering effects.

The Niemann-Pick C1–like 1 cholesterol uptake receptor is an entry factor for the hepatitis C virus, according to this report. Ezetimibe, a drug that targets this receptor and is approved for use in humans, inhibits infection by the hepatitis C virus in a mouse model, highlighting the therapeutic potential of this discovery.