Better late than never for schizophrenia gene targeting

Researchers from Columbia University have demonstrated that correcting mutations in the schizophrenia risk gene SetD1 in adult mice reversed cognitive impairments, suggesting that, like a number of other brain disorders, schizophrenia's malfunctions begin in early development, but remain in place via ongoing active processes rather than reaching a point of no return. SetD1a codes for an epigenetic enzyme that methylates specific lysines on histones, and loss-of-function mutations strongly increase the risk of schizophrenia in carriers. In their work, the team showed that lack of SetD1 led to cognitive deficits, but when they reinstated SetD1 activity in adulthood, those deficits were partially reversible. Inhibiting lysine demethylase 1 (LAS1), whose activity counteracts that of SetD1, also restored cognitive function. Partial restoration of cognitive deficits might have resulted from the incomplete reinstatement of SetD1a expression or could reflect a partial developmental contribution requiring additional earlier interventions, the authors wrote. "These limitations notwithstanding and consistent with continued plasticity in the adult brain, our findings indicate that adult Setd1a function reinstatement has substantial effects on ameliorating cognitive deficits, highlighting a broad window of therapeutic opportunity." They reported their findings in the Oct. 9, 2019, issue of Neuron.

Mitochondrial mutations hamper nuclear DNA repair

Mitochondrial mutations can contribute to premature aging, and the mechanism by which they do so is thought to be decreased energy and increased ROS production. Now, researchers from the University of Eastern Finland and the University of Helsinki have shown that mitochondrial mutations also siphoned resources from genomic DNA repair, leading to genome maintenance problems similar to those seen with defects in DNA repair enzymes. "Our data indicate that defects in mtDNA replication can challenge nuclear genome stability," the authors wrote. "Therefore, through their destabilizing effects on the nuclear genome, mtDNA mutations are indirect contributors to organismal ageing, suggesting that the direct role of mtDNA mutations in driving ageing-like symptoms might need to be revisited." They reported their findings in the Oct. 7, 2019, issue of Nature Metabolism.

Reservoir grows when ART starts

Researchers at the University of Cape Town and the University of North Carolina have discovered that most of the latent HIV reservoir of infected but nondividing cells that is impervious to current antiretroviral therapy, and the major obstacle to HIV cures, is formed around the initiation of antiretroviral therapy (ART), rather than throughout the course of HIV infection. Individuals who start ART later in the course of HIV infection have a larger, more genetically diverse viral reservoir than those who start ART shortly after infection, and that has been interpreted to mean that the reservoir is formed and increases throughout the natural course of HIV infection. However, when the team sequenced reservoir samples from different timepoints before ART initiation, and compared them to samples acquired after ART initiation, they found that the majority of post-ART viruses were similar to those circulating just before ART initiation. The authors concluded that "ART alters the host environment in a way that allows the formation or stabilization of most of the long-lived latent HIV-1 reservoir, which points to new strategies targeted at limiting the formation of the reservoir around the time of therapy initiation." They reported their results in the Oct. 9, 2019, issue of Science Translational Medicine.

Accidental immunity gives rotavirus insight

Researchers from Georgia State University have demonstrated that segmented filamentous bacteria (SFBs), a type of commensal bacteria, protected mice from rotavirus (RV) infection. Despite the existence of a vaccine, rotavirus causes 200,000 deaths in children under 5 annually. The authors realized that when they bred commercially acquired, immunodeficient mice in their colony, those mice acquired resistance to chronic rotavirus infection. Fecal transfer experiments demonstrated that the protection was mediated in a component of the microbiome, and attempts to isolate the specific component suggested that the protection derived from SFBs. "An improved understanding of the mechanisms by which SFBs promote RV resistance may ultimately lead to new approaches to prevent and treat viral infections," the authors wrote. "Investigation of the effect of SFBs on the host may reveal previously unappreciated innate antiviral signaling pathways, whereas the microbiota itself might be a possible source of antiviral agents." They reported their findings in the Oct. 10, 2019, issue of Cell.

Ironing out regional differences affects anxiety

Investigators at Southern Medical University have shown that brain iron transport affected both the actions of the anxiety drug diazepam, and the behavioral effects of stress. Iron levels vary by brain region, and iron accumulates in distinct brain regions during healthy aging on the one hand and in Parkinson's disease on the other. The researchers identified two major iron transport pathways in the brain and demonstrated that increasing transport via one of those pathways, which runs from the hippocampus to the medial prefrontal cortex, reduced anxious behavior in response to stress. Diazepam increased iron transport along the same pathway. "Taken together, these findings provide key insights into iron metabolism in the brain and identify the mechanisms underlying iron transport in the brain as a potential target for development of novel anxiety treatments," the authors wrote. Their work appeared in the Oct. 7, 2019, online issue of Nature Chemical Biology.

Testosterone replacement cells a step closer

Scientists at the University of Southern California have developed protocols that allowed them to generate either cortisol-producing adrenal-like cells or testosterone-producing Leydig-like cells from induced pluripotent stem cells (iPSCs). Leydig cells produce testosterone in response to luteinizing hormone, and low testosterone levels in men are linked to a number of different pathologies. Unfortunately, testosterone replacement is linked to some of the same pathologies, as uncoupling testosterone production from luteinizing hormones is problematic in itself. Transplanting Leydig cells could offer a more physiological approach to testosterone replacement, but so far, there is no easy way to generate differentiated Leydig cells from easily obtainable stem cells. The team developed a protocol to generate either Leydig-like cells or adrenal-like cells from iPSCs. "This bidirectional approach offers insights into the events specifying different steroidogenic cell populations sharing developmental origins," they wrote. "More importantly, our study provides a way to generate possible transplantation materials for clinical therapies. Human Leydig-like cells could also be useful for in vitro studies of testicular development and pathologies of testis-relevant diseases, and for the discovery of new drugs inducing androgen formation for hypogonadism treatment." Their work appeared in the Oct. 7, 2019, online issue of the Proceedings of the National Academy of Sciences.

P63 is behind thalidomide birth defects

Despite its fame, the molecular mediators of birth defects caused by fetal exposure to thalidomide remain unknown. It has become clear over the past few years, though, that thalidomide directly affects cereblon, part of a protein complex that adds ubiquitin destruction markers to proteins. Thalidomide binding to cereblon alters the proteins that are tagged by the cereblon-containing complex. Now, researchers at Tokyo Medical University have demonstrated that the transcription factor p63 is among the targets of cereblon, and that the interaction between thalidomide and p64 was responsible for developmental defects in zebrafish. The authors wrote that "these results may contribute to the invention of new thalidomide analogs lacking teratogenic activity." They reported their findings in the Oct. 7, 2019, online issue of Nature Chemical Biology.

For antioxidants, bad news is worse than good news is good

Researchers at INSERM have demonstrated that antioxidant treatment increased the risk of developing lung cancer in mouse models. Antioxidants were once considered to protect from cancer, an opinion that is still widely held in the general public. In recent years there has been increasing evidence that antioxidants can accelerate the growth of existing tumors, but to date, whether they also increase the risk of developing tumors in the first place has been unknown. Antioxidants are beneficial for the treatment of lung fibrosis, and the authors treated mice lacking the transcription factor JunD, which are prone to lung fibrosis, with the antioxidant n-acetylcysteine (NAC). They found that "NAC treatment decreased lung oxidative damage and cell senescence and protected from lung emphysema but concomitantly induced the development of lung adenocarcinoma in 50% of JunD-deficient mice and 10% of aged control mice. This finding constitutes the first evidence to our knowledge of a carcinogenic effect of antioxidant therapy in the lungs of aged mice with chronic lung oxidative stress and warrants the utmost caution when considering the therapeutic use of antioxidants." Their work appeared in the Oct. 3, 2019, online issue of JCI Insight.

Anticoagulants prevent AD symptoms

Investigators from the Centro Nacional de Investigaciones Cardiovasculares (CNIC) have demonstrated that long-term treatment with the anticoagulant drug dabigatran prevented pathological brain changes and cognitive decline in a mouse model of Alzheimer's disease (AD). AD is associated with increased pro-clotting activity, including the formation of clots in the brain that interact with amyloid plaques. The team tested whether such clotting contributed to AD pathology by treating transgenic AD mice and wild-type littermates with dabigatran for a year. They found that "anticoagulation with dabigatran prevented memory decline, cerebral hypoperfusion, and toxic fibrin deposition in the AD mouse brain. In addition, long-term dabigatran treatment significantly reduced the extent of amyloid plaques, oligomers, phagocytic microglia, and infiltrated T cells... Long-term anticoagulation with dabigatran inhibited thrombin and the formation of occlusive thrombi in AD; preserved cognition, cerebral perfusion, and BBB function; and ameliorated neuroinflammation and amyloid deposition in AD mice. Our results open a field for future investigation on whether the use of direct oral anticoagulants might be of therapeutic value in AD." They reported their findings in the Oct. 7, 2019, online issue of the Journal of the American College of Cardiology.

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