Deficiency of the antidiuretic hormone arginine vasopressin (AVP) underlies diabetes insipidus, which is characterized by the excretion of abnormally large volumes of dilute urine and persistent thirst. In this issue of the JCI, Shi et al. report that Sel1L-Hrd1 ER–associated degradation (ERAD) is responsible for the clearance of misfolded pro–arginine vasopressin (proAVP) in the ER. Additionally, mice with Sel1L deficiency, either globally or specifically within AVP-expressing neurons, developed central diabetes insipidus. The results of this study demonstrate a role for ERAD in neuroendocrine cells and serve as a clinical example of the effect of misfolded ER proteins retrotranslocated through the membrane into the cytosol, where they are polyubiquitinated, extracted from the ER membrane, and degraded by the proteasome. Moreover, proAVP misfolding in hereditary central diabetes insipidus likely shares common physiopathological mechanisms with proinsulin misfolding in hereditary diabetes mellitus of youth.
Daniel G. Bichet, Yoann Lussier
Glaucoma is a leading cause of blindness, with an estimated world-wide prevalence of 3.5% in members of the population older than 40 years of age. Elevated intraocular pressure as the result of abnormal resistance to aqueous humor drainage is a major contributing, and the only preventable, factor in glaucoma development. Schlemm’s canal (SC), a lymphatic-like vessel encircling the anterior portion of the eye, plays a key role in promoting aqueous humor outflow and maintenance of normal intraocular pressure. The risk of developing glaucoma increases with age; therefore, understanding mechanisms of SC maintenance and how aging affects SC function are of special importance, both for prevention and novel treatment approaches to glaucoma. Using a compelling array of genetic models, Kim et al. report in this issue of the JCI that continuous angiopoietin/TIE2 signaling is required for maintaining SC identity and integrity during adulthood and show that its age-related changes can be rescued by a TIE2 agonistic antibody.
Jeremiah Bernier-Latmani, Tatiana V. Petrova
Chromatin modification influences gene expression by either repressing or activating genes, depending on the specific histone mark. Chromatin structure can also influence alternative splicing of transcripts; however, the mechanisms by which epigenetic marks influence splicing are poorly understood. A report in the current issue of the JCI highlights the biological importance of the coordinated control of alternative pre-mRNA splicing by chromatin structure and transcriptional elongation. Yuan et al. found that mutation of the histone methyl transferase SEDT2 affects alternative splicing fates of several key regulatory genes, including those involved in Wnt signaling. As a consequence, loss of SEDT2 in the intestine aggravated Wnt/β-catenin signaling effects, thereby leading to colorectal cancer.
Alberto R. Kornblihtt
Transplantation of human neural stem cells has long been proposed as a potential strategy for treating CNS injury and disease; however, application of this approach has had limited therapeutic benefit. Yet compared with rodents and other experimental mammals, humans have a relatively long time window for development of the brain and spinal cord. In this issue of the JCI, Lu and colleagues asked whether the results of neural stem cell transplantation might be improved by accommodating the protracted development of human neural cells. They used a rodent model of spinal cord injury, in which human neural progenitor cells were transplanted at the site of damage. While there was no observable benefit at early time points after transplantation, both anatomic and functional improvements in the injured animals emerged over the course of a year. In particular, the human progenitor cell population differentiated, matured, and integrated into the rodent spinal cords over a time frame that aligned with the normal development of these cells in humans. This study demonstrates that neural stem cells may offer significant therapeutic benefit after CNS injury; however, this process may take time and demands patience on the part of investigators, patients, and clinicians alike.
Steven A. Goldman
Leukotrienes are proinflammatory lipid mediators that have been shown to be upregulated in several diseases, including asthma, aspirin-exacerbated respiratory disease (AERD), inflammatory bowel disease, and acute respiratory distress syndrome. Leukotrienes have been explored as therapeutic targets for these diseases and others; however, leukotriene inhibitors have had limited success in the clinic. There are noted differences in the incidence of leukotriene-mediated diseases in males and females, but sex as a factor in the response to leukotriene inhibitors has not been fully explored. In this issue of the JCI, Pace and colleagues present evidence that there are sex-specific differences in the effectiveness of certain leukotriene inhibitors and link the differences in response to the presence of androgens. The results of this study indicate that sex needs to be taken into consideration in the future evaluation of leukotriene inhibitors to treat disease.
Lewis J. Smith
The blood brain barrier (BBB) and the glia limitans serve to prevent the migration of cells and other large molecules from the blood into the CNS. Neuroinflammatory diseases are characterized by disruption of the BBB and increased leukocyte infiltration into the CNS. In this issue of the JCI, Horng and colleagues demonstrate that astrocytes of the glia limitans induce tight junction formation in response to inflammatory cues, thereby tightening the border to limit the number of activated T cells infiltrating the CNS. Moreover, preventing the formation of this inducible barrier in mice increased disease severity in models of neuroinflammation. Together, the results of this study indicate that the inducible barrier of the glia limitans should be further explored as a therapeutic target.
Francisco J. Quintana
Proteinopathies are characterized by the accumulation of misfolded proteins, which ultimately interfere with normal cell function. While neurological diseases, such as Huntington disease and Alzheimer disease, are well-characterized proteinopathies, cardiac diseases have recently been associated with alterations in proteostasis. In this issue of the JCI, Fang and colleagues demonstrate that mice with cardiac-specific deficiency of the co-chaperone protein BCL2-associated athanogene 3 (BAG3) develop dilated cardiomyopathy that is associated with a destabilization of small HSPs as the result of a disrupted interaction between BAG3 and HSP70. Together, the results of this study suggest that strategies to upregulate BAG3 during cardiac dysfunction may be beneficial.
Wataru Mizushima, Junichi Sadoshima
Coronary revascularization is an effective means of treating ischemic heart disease; however, current therapeutic revascularization strategies are limited to large caliber vessels. Because the mammalian heart scars following cardiac injury, recent work showing that cardiac fibroblasts can transdifferentiate into new coronary endothelium raises a new and exciting approach to promoting endogenous revascularization following cardiac injury. In this issue of the JCI, He et al. report on their employment of a battery of lineage-tracing tools to address the developmental origins of fibroblasts that give rise to new endothelial cells. Surprisingly, cardiac fibroblasts did not appear to contribute appreciably to regeneration of cardiac endothelium. Instead, cardiac endothelial cells were likely to proliferate and generate new endothelium following injury. As these conclusions diverge from prior findings, additional work will be required to understand the sources that generate cardiac endothelium in new blood vessels after injury. Clarification of the origins of coronary endothelial cells during cardiac repair is essential for identifying improved approaches to revascularizing damaged myocardium in patients with ischemic heart disease.
Ravi Karra, Agoston O. Walter, Sean M. Wu
Overconsumption of fructose and other sugars has been linked to nonalcoholic fatty liver disease (NAFLD); however, the sugar-associated effects that lead to disease are poorly defined. In this issue of the JCI, Zhang and colleagues show that the carbohydrate response element–binding protein (ChREBP) coordinates an adaptive response to a high-fructose diet in mice and that loss of this transcription factor leads to hepatic inflammation and early signs of fibrosis. Intriguingly, ChREBP-dependent effects were due to an exaggerated activation of the proapoptotic arms of the endoplasmic reticulum stress response that is probably secondary to inappropriate derepression of cholesterol biosynthesis. These findings suggest that a previously unknown link exists between ChREBP and the regulation of cholesterol synthesis that affects liver injury.
Angela M. Hall, Brian N. Finck
While antiretroviral therapy (ART) can reduce HIV-1 to undetectable levels, the virus generally reappears if treatment is stopped. Resurgence of the virus is due to the reactivation of T cells harboring latent integrated provirus, and recent studies indicate that proliferation of these latently infected cells helps maintain the HIV-1 reservoir. In this issue of the JCI, Lee et al. evaluated CD4+ T cell subsets to determine whether certain populations are more likely to harbor full-length, replication-competent provirus. The authors identified an enrichment of clonally expanded Th1 cells containing intact HIV-1 proviruses, suggesting that this polarized subset contributes to the persistence of the reservoir. Strategies to target these provirus-harboring cells need to be considered for future therapies aimed toward HIV-1 cure.
Kyungyoon J. Kwon, Robert F. Siliciano
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