MicroRNAs in kidney physiology and disease

 Abstract

MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate gene expression. They have important roles during kidney development, homeostasis and disease. In particular, miRNAs participate in the onset and progression of tubulointerstitial sclerosis and end-stage glomerular lesions that occur in various forms of chronic kidney disease (CKD). Therefore, miRNAs represent potential new therapeutic targets for a debilitating disease that continues to increase in prevalence worldwide and for which fully effective therapies are lacking. Several lines of research aimed at improving common CKD diagnostic tools and avoiding invasive kidney biopsies have also identified circulating miRNAs as possible diagnostic and even prognostic biomarkers of kidney disease. This Review discusses current understanding of the function of miRNAs in CKD, focusing on functions specifically involved in the transforming growth factor β1 pathway, which is activated in CKD. miRNAs that, according to available evidence, seem to be involved in diabetic nephropathy, IgA nephropathy, lupus nephritis, polycystic kidney disease and graft rejection, are also discussed.

 Key points

• MicroRNAs (miRNAs) are key players in kidney development and physiology
• Transforming growth factor β1 is a major regulator of kidney fibrosis; its signalling is finely regulated by miRNAs
• miRNAs contribute to both the induction and progression of chronic kidney disease (CKD)
• Current translational research on miRNAs in kidney disease is mainly focused on developing reliable biomarkers for diagnosis and prognosis of CKD and renal transplantation
• miRNAs represent novel therapeutic targets for CKD, but delivery and safety issues must be taken into account before translation into clinical practice

Introduction

Chronic kidney disease (CKD) is an important public health problem that is closely linked to major non-communicable diseases such as diabetes mellitus and hypertension.¹ Less common causes of CKD are hereditary diseases such as polycystic kidney disease (PKD), IgA nephropathy (IgAN) and lupus nephritis, or herbal and environmental toxins. Regardless of the disease aetiology, progression of CKD results in tubulointerstitial and glomerular fibrosis owing to excessive deposition of extracellular matrix (ECM). Other key features of CKD are inflammatory cell infiltration, tubular cell atrophy, mesangial cell hypertrophy and podocyte apoptosis.² All of these pathological events are mainly instigated by the cytokine transforming growth factor β1 (TGF-β1).³

 

Current therapies that target the renin–angiotensin–aldosterone system⁴ are not always effective in halting progression to end-stage renal disease, a condition that requires renal replacement therapy by dialysis or kidney transplantation. Blockade of TGF-β1 signalling using TGF-β1 neutralizing antibodies or specific inhibitors of TGF-β1 receptors might be a promising therapeutic approach for CKD as these strategies have been shown to attenuate renal fibrosis in various animal models.⁵ The success of these approaches in preclinical studies has prompted the search for therapies that interfere with the epigenetic regulation of TGF-β and genes involved in the TGF-β signalling pathway. In this context, non-coding RNA species, including microRNAs (miRNAs), have been widely implicated in the pathogenesis and progression of CKD, particularly in the regulation of TGF-β1-mediated fibrosis. Correction of miRNA expression by in vivo delivery of miRNA mimics or inhibitors has therefore emerged as a promising novel therapeutic strategy for the treatment of CKD. In addition, several lines of current research aimed at improving common CKD diagnostic tools and avoiding invasive kidney biopsies have identified circulating miRNAs as possible diagnostic and even prognostic biomarkers.^{6, 7} This Review focuses on current research investigating the roles of miRNAs in normal kidney physiology and diseases; particular attention is given to the TGF-β1 pathway and its regulation by miRNAs.

Biogenesis and function of miRNAs

miRNAs are epigenetic regulators of gene expression that are able to modulate several cellular processes, from development to disease conditions. The human miRNAome is composed of 1,881 precursors and 2,588 mature miRNAs, which regulate at least 60% of protein-coding genes.⁸ Since 2010, the number of miRNAs included in miRBase has grown by approximately two-thirds owing to the advent of small RNA deep-sequencing techniques.⁹

 

Here, we briefly mention the key points of miRNA biogenesis and function, as these processes are described thoroughly elsewhere.^{10, 11} Transcription of miRNAs occurs from individual or clustered genes (that is, the miR-194–192 cluster), although some miRNAs can be encoded from distinct genomic loci.¹² Genes encoding miRNAs are located in non-coding sequences or in introns of either protein-coding genes (miR-trons) or non-coding RNA.¹³ Intronic miRNAs are usually coordinately expressed with their host gene and most of the time they both affect the same signalling pathway.^{14, 15, 16}

 

RNA polymerase II transcribes miRNAs in the nucleus as long capped and polyadenylated hairpin transcripts, called primary miRNAs (pri-miRNAs). These are processed into smaller ~70 nucleotide stem–looped structures, called precursor miRNAs (pre-miRNAs) by the ribonuclease III-like enzyme Drosha together with the microprocessor complex subunit DGCR8. Pre-miRNAs are then exported to the cytoplasm by exportin-5/GTP-binding nuclear protein Ran, where the ribonuclease Dicer yields 22 nucleotide miRNA duplexes consisting of the guide and passenger strands (miRNA:miRNA*). The guide strands are finally assembled into the RNA-induced silencing complex (RISC) and bind through their 'seed sequence' (nucleotides 2–8) to fully or partially complementary sites within the 3′ untranslated region of target mRNAs. miRNAs rarely bind to the coding regions of mRNA or genomic DNA, including promoter regions.¹⁷ Target recognition by miRNAs leads to mRNA translational repression and/or mRNA deadenylation and decay,^{18, 19} although positive regulation has been described in a few cases (Figure 1).^{20, 21} Beyond the simplistic concept that miRNAs act as repressors of a single transcript, emerging evidence indicates that they are modulators of many hundreds of proteins often involved in related signalling pathways.^{22, 23}

Figure 1: Interplay between TGF-β1/Smad signalling and the miRNA machinery. 

TGF-β1/Smad signalling can modulate miRNA expression by regulating transcription and/or facilitating the processing of pri-miRNA into pre-miRNA in the nucleus. Pre-miRNA is exported to the cytoplasm where it is processed into the final mature miRNA, which is loaded into the RISC. Mature miRNA guides the RISC to silence target mRNAs through mRNA cleavage, translational repression or deadenylation. Rarely, transcriptional activation can occur. Abbreviations: Co-Smad, common mediator Smad; miRNA, microRNA; P, phosphorylation; pre-miRNA, precursor miRNA; pri-miRNA, primary miRNA; RISC, RNA-induced silencing complex; R-Smad, receptor-regulated Smad; SBS, Smad binding site; TGF-β1, transforming growth factor β1; TGFBR1, TGF-β receptor type-1; TGFBR2, TGF-β receptor type-2; UTR, untranslated region.

miRNAs are usually stable with a long half-life, but individual miRNAs can undergo rapid decay in specific cellular contexts in the presence of particular environmental stimuli or cellular factors. Of note, the presence of certain sequences in miRNAs that determine decay rate, together with several ribonucleases that degrade miRNAs, have been identified.²⁴

miRNAs also have a key role as regulators of cellular crosstalk.⁶ They can be actively secreted into the extracellular microenvironment or into body fluids and captured by other cells, thus altering their transcriptional programme. In addition, circulating miRNAs can be derived from apoptotic cells, with the likely purpose of carrying alarm signals from apoptotic cells to other cells.⁶ miRNAs circulate in blood, urine and other body fluids either packaged into microvesicles and/or exosomes, or transported by RNA-binding proteins (Argonaute2 complexes) and lipoproteins, which protect them from degradation by ribonucleases.⁶ The consequent stability of miRNAs in biological fluids, together with the fact that miRNAs can be repeatedly collected by non-invasive means and detected with high accuracy and specificity by amplification methods, renders miRNAs potentially better biomarkers than proteins and mRNAs. However, isolation and quantification of miRNAs is time-consuming and expensive, and further optimization of these procedures is required before they can be used in routine clinical practice.

miRNAs in development and physiology

Analyses of miRNA expression profiles have identified a set of miRNAs expressed mainly in the adult human kidney (including miR-215, miR-146a and miR-886); other miRNAs, such as miR-192, miR-194, miR-21, miR-200a, miR-204 and let-7a–g, are enriched in the kidney as well as in other organs.^{14, 25, 26} However, some discordant findings regarding miRNA expression profiles have been reported, probably owing to use of different detection methods and to differences in the intrinsic nature of the analysed samples. The picture is further complicated by the fact that expression levels of selected miRNAs differ between fetal and adult kidneys, suggesting that besides being tissue-specific, miRNA expression is specific to developmental stage.²⁷

The generation of mouse models with conditional knockdown of miRNA-processing enzymes or knockdown of specific miRNAs in various cell lineages has enabled the roles of miRNAs during kidney development and homeostasis to be studied. In nephron progenitor cells, conditional deletion of Dicer results in their apoptosis—mediated by the proapoptotic protein Bim—and in the premature termination of nephrogenesis.^{28, 29} Ablation of the miR-17~92 cluster, composed of miRNAs normally expressed in the developing kidney with well-known roles in development, leads to defective proliferation of progenitor cells and reduced numbers of developing nephrons.³⁰ Mice deficient in miR-17~92 are characterized by renal hypodysplasia and develop glomerular dysfunction and proteinuria.³⁰

In ureteric buds, impaired miRNA processing leads to excessive cell proliferation and apoptosis accompanied by disrupted ciliogenesis within the epithelium of ureteric buds and consequent development of renal cysts.^{29, 31} In addition, one study suggested that miRNAs modulate later stages of renal tubule maturation as removal of Dicer from maturing renal tubules and collecting ducts leads to the formation of tubular and glomerular cysts in mice through a mechanism that probably involves modulation of Pkd1 gene dosage by miRNAs.³²

miRNAs also have a key role in podocyte homeostasis. Indeed, podocyte-specific deletion of Dicer or Drosha in the developing kidney causes disruption of the glomerular filtration barrier, leading to proteinuria and collapsing glomerulopathy with glomerular and tubulointerstitial fibrosis.^{33, 34, 35, 36, 37} Moreover, miRNA processing is important for maintenance of adult podocyte function and differentiation as selective deletion of Drosha in adult mice results in collapsing glomerulopathy,³⁷ whereas inactivation of Dicer in postnatal proximal tubules does not affect their histology or function and protects mice from renal ischaemia–reperfusion injury.³⁸

miRNAs are also involved in regulating renal physiology, from the control of blood pressure to the maintenance of whole-body fluid and electrolyte homeostasis. The role of miRNAs in blood pressure control was ascertained by generation of mice with specific inactivation of Dicer in renin-expressing juxtaglomerular cells, which leads to loss of these cells accompanied by reduced plasma renin concentration, hypotension and kidney fibrosis.^{39, 40} Several miRNAs are modulated by hypertonic conditions and have a key role in the control of osmolarity balance by regulating Na⁺ and K⁺ levels in the different portions of the nephron. miR-192 suppresses the Na⁺/K⁺-ATPase β1 subunit gene in human renal epithelial cells,⁴¹ and in the distal nephron it inhibits the serine/threonine kinase WNK1, a protein that is essential for the coordinated regulation of electrolyte transport in the kidney.⁴² Regulation of Na⁺ transport by miRNAs has been ascertained in the mouse cortical collecting duct where aldosterone reduces the expression of a subset of miRNAs that target ankyrin-3. In turn, overexpression of ankyrin-3 increases sodium transport mediated by the epithelial Na channel.⁴³ Moreover, renal medullary cortical collecting duct cells exposed to high Na⁺ concentration are characterized by reduced levels of miR-200 and miR-717 in association with increased levels of their common target NFAT5,⁴⁴ which controls the cellular response to osmotic stress. miRNAs are also able to regulate K⁺ secretion. Indeed, in the cortical collecting duct, high dietary K⁺ intake stimulates the transcription of miR-802 and miR-194, which regulate ROMK channel activity by targeting caveolin-1 (a negative regulator of the ROMK channel)⁴⁵ and intersectin-1 (involved in mediating the WNK-induced endocytosis of the ROMK channel),⁴⁶ respectively. Finally, in the thick ascending limb of Henle, miR-9 and miR-374 regulate the expression of claudin-14, which is critical for Ca²⁺ reabsorption in the kidney.⁴⁷ Interestingly, the transcriptional levels of both miRNAs are directly regulated by the Ca²⁺-sensing receptor CASR.⁴⁸

Figure 2: miRNA-regulatory networks in proximal tubular epithelial cells and mesangial cells in response to TGF-β1, and in podocytes in response to TGF-β1 and high glucose.

Up and down black arrows represent upregulated and downregulated, respectively. miRNA-dependent signalling loops through which TGF-β1 amplifies its signal are shown in green. Abbreviations: ECM, extracellular matrix; HDAC, histone deacetylase; miRNA, microRNA; TGF-β1, transforming growth factor β1; TGFBR1, TGF-β receptor type-1.

miRNAs in immune diseases

IgA nephropathy (IgAN) is characterized by aberrant glycosylation of IgA1, a reaction catalysed in part by C1GALT1, which has been proposed to be a target of miR-148b. miR-148b is upregulated in peripheral blood mononuclear cells (PBMCs) isolated from patients with IgAN, and patients carrying the 1365G/G genotype in the miR-148b-binding site of C1GALT1 have increased C1GALT1 binding affinity for miR-148b and consequently lower enzyme expression (Table 1).¹⁰⁵

Global miRNA expression analysis in kidney biopsy samples from patients with IgAN found that dysregulated levels of miRNAs related to fibrosis (downregulation of miR-200c and upregulation of miR-192, miR-141 and miR-205)¹⁰⁶ and to the immune response (upregulation of miR-155 and miR-146a)¹⁰⁷ correlated with disease severity and progression. Moreover, glomerular endothelial cells of patients with IgAN are characterized by reduced expression of miR-223, which causes glomerular endothelial proliferation, a pathological hallmark of IgAN.¹⁰⁸ Low levels of miR-223 were also found in circulating endothelial cells, providing a possible non-invasive method for evaluating the severity of IgAN (Table 1). Other potential biomarkers of IgAN are miR-155,¹⁰⁹ miR-146a,¹⁰⁹ miR-17¹⁰⁴ and miR-93—which are found at increased levels—and miR-29b and miR-29c—which are found at decreased levels—in the urine of patients with IgAN.¹⁰⁹

miRNA dysregulation also has a key role in lupus nephritis, an autoimmune disorder with a complex pathophysiology. miRNA expression analysis in kidney biopsy samples of patients with class II lupus nephritis (characterized by pure mesangial involvement), identified 36 upregulated and 30 downregulated miRNAs compared with healthy controls.¹¹⁰ miR-150 has also been demonstrated to promote renal fibrogenesis in lupus nephritis (Table 1).^{111, 112} miR-150 targets SOCS1, a negative regulator of the JAK/STAT signalling pathway, which regulates a wide range of genes involved in cell proliferation, inflammation and fibrosis. In human mesangial cells and pTECs, TGF-β1 upregulates miR-150, resulting in decreased expression of SOCS1 and increased production of profibrotic proteins. SOCS1-knockout mice spontaneously develop a lupus-like disease; likewise, the kidneys and in particular the tubular cells of patients with fibrosing lupus nephritis are characterized by increased expression of miR-150 in association with lower levels of SOCS1.¹¹¹

In patients with lupus nephritis of differing severities, a correlation was identified between clinical disease severity and glomerular and tubulointerstitial expression of miR-638, miR-198 and miR-146.¹¹³ Analysis of miRNA expression profiles in plasma,¹¹⁴ urinary sediment¹¹⁵ and PBMCs¹¹⁶ revealed a subset of miRNAs associated with lupus nephritis (miR-342-3p, miR-223 and miR-20a in plasma, miR-221 and miR-222 in urinary sediment, and miR-371-5p, miR-1224-3p and miR-423-5p in PBMCs), which are potential promising disease biomarkers.¹¹⁷

miRNAs in kidney transplantation

miRNA profiling could be a promising tool for monitoring the status of transplanted kidneys, which despite advances in immunosuppressive therapy can undergo acute rejection (an event that is becoming increasingly less common) or chronic rejection. Two research groups have identified miRNAs that were differentially expressed in biopsy samples from the kidneys of patients with acute rejection, although no overlapping miRNAs were found.^{127, 128} In particular, Anglicheau and colleagues demonstrated that increased intragraft levels of miR-142-5p, miR-155 and miR-223, probably derived by graft-invading immune cells, and decreased levels of miR-10b, miR-30a-3p and let-7c, expressed by resident renal cells, were predictive of renal graft function.¹²⁸ One study identified miRNA signatures in kidney biopsy samples that were able to distinguish between acute cellular and humoral rejection and delayed graft function.¹²⁹ Of note, Lorenzen et al.¹³⁰ analysed miRNA expression in the urine of patients with acute rejection and proposed miR-210 as a novel biomarker of acute rejection and predictor of long-term graft function.

 

Interestingly, analysis of a blood-derived miRNA signature of drug-free tolerant patients after kidney transplantation identified eight modulated miRNAs. Among these miRNAs, overexpression of miR-142-3p in PBMCs was correlated with drug-free tolerance, probably owing to the negative regulation of TGF-β signalling by miR-142-3p. Thus, miR-142-3p expression represents a promising predictor of patients who could reduce or even avoid immunosuppressive therapies.¹³¹

 

Three reports studied miRNA changes during chronic rejection characterized by interstitial fibrosis and tubular atrophy (IF/TA). miR-142-3p, miR-204 and miR-211 were differentially expressed in kidney biopsy samples and urine of patients with chronic rejection characterized by IF/TA compared with patients with normal histology and a functioning allograft.¹³² A subsequent study confirmed miR-142-3p overexpression in biopsy samples with IF/TA, and also reported dysregulation of miR-21, miR-142-5p, the cluster comprising miR-506 on chromosome X, miR-30b and miR-30c in these samples.¹³³ Investigation of miRNA expression in urinary cell pellets from patients diagnosed with chronic rejection with IF/TA compared with those with normal renal function identified 22 differentially expressed miRNAs, mainly associated with inflammation.¹³⁴ More importantly, these researchers identified a subset of miRNAs (miR-200b, miR-375, miR-423-5p, miR-193b and miR-345), which are promising biomarkers for monitoring graft function and anticipating progression to chronic rejection, as they were differentially expressed between the two groups soon after kidney transplantation but before histological injury was evident.¹³⁴

Potential uses of miRNAs for therapy

Mature miRNAs possess distinct features that make them potentially suitable as therapeutic agents, including their short sequence and their high homology across multiple vertebrate species. Manipulation of the activity of specific miRNAs in the kidney can be achieved by in vivo delivery of mimics to restore miRNA levels or inhibitors to block miRNA function. miRNA mimics are double-stranded synthetic oligonucleotides that accomplish the endogenous functions of the miRNA of interest, but following chemical modifications possess increased stability and are efficiently taken up by cells. The most widely adopted strategy so far to block miRNA function is with chemically modified oligonucleotides (anti-miRs) designed against the mature miRNA sequence that are stable in circulation and are cell permeable (2′-O-methyl-group-modified oligonucleotides or locked nucleic acid anti-miRs). In addition to anti-miRs, miRNA inhibition can be achieved by expression of miRNA-target sequences able to capture pathogenic miRNAs (miRNA sponge), short hairpin RNA plasmids to abrogate miRNA expression via RNA interference, or using oligonucleotides complementary either to the 3′ untranslated region of the target mRNA binding site sequence (masking approach) or to the sequence of the miRNA (erasers).

 

Many studies in experimental animal models have focused on the therapeutic potential of miRNAs in CKD and promising results in halting renal fibrosis have been obtained by knocking down miR-21,^{22, 65, 92} miR-29c,⁹⁹ miR-214,²³ miR-433,⁹⁴ and miR-192^{69, 76} or overexpressing miR-29b (Table 2).^{66, 80} Successful kidney transfection was achieved by intraperitoneal, intravenous or subcutaneous injection of either mimics or inhibitors or, more frequently, by intravenous injection of plasmids expressing miRNAs or short-hairpin RNAs.

 

However, many obstacles must be overcome before miRNA-based therapies for CKD can be translated into clinical practice, including delivery methods and safety concerns. Indeed, the target miRNA should be kidney-specific in order to avoid any potential adverse effects in other tissues and organs, and should affect only one target (or targets acting in the same pathway) to avoid effects on unintended templates, as in the case of miR-21, the knockdown of which induces cell death in addition to halting renal fibrosis.⁶⁵ So far, these limitations have been partially overcome either by local administration of miRNA-based drugs or by using vectors containing kidney-specific and inducible promoters.

Conclusions

 

The importance of miRNAs in the kidney field is increasingly recognized as they enable researchers to understand in-depth the pathways that have a role in kidney physiology and disease. They can also provide an explanation for divergent transcriptomic and proteomic data. Moreover, an miRNA-based therapy that either restores or blocks miRNA expression and activity is very attractive, especially now that the first miRNA-targeted drug (miravirsen for the treatment of hepatitis C) has entered a phase II clinical trial.¹³⁵ So far, the potential of miRNAs as an effective antifibrotic therapy has been demonstrated only in experimental models of CKD because many safety concerns must be resolved, from the delivery method to the adverse effects on alternative templates. Instead, a more impending application is the detection and quantification of circulating miRNAs as a novel non-invasive, repeatable method to identify and monitor the degree of disease. However, because most miRNAs are highly pleiotropic and act differently depending on the cell type, a single miRNA is unlikely to be able to diagnose and predict a form of CKD. Instead, a network of correlated miRNAs must be considered.

 

Nature Reviews Nephrology | Review

Piera Trionfini^1, Ariela Benigni^1, Giuseppe Remuzzi^1,

Published online 11 November 2014

                                                                                                                                                                                                                                                                                                                                                                                                                             

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Mother’s Microbes Protect Baby’s Brain

Bacteria in the gut of a pregnant mouse strengthen the blood-brain barrier of her developing fetus.

V. ALTOUNIAN/SCIENCE TRANSLATIONAL MEDICINEThe brain—the most exalted and enigmatic of organs, which is closed off from the rest of the body by a largely impermeable barrier—could not seem more disconnected from the intestine. Yet, according to a paper published today (November 19) in Science Translational Medicine, it’s thanks to the contents of the gut—specifically, the resident bacteria—that the mouse brain’s impermeable barrier develops properly, both before and after birth.

 

“It’s absolutely fascinating to think that gut bacteria can control permeability of the blood-brain barrier,” said Caltech microbiologist Sarkis Mazmanian who was not involved in the study. “Many neuroscientists staunchly believe that the blood-brain barrier is an incredibly impermeable membrane to many molecules and . . . would hardly believe that gut bacteria would control such an integral part of our neurobiology.”

 

The blood-brain barrier (BBB), which shields the organ from blood-borne infections, toxins, and more, is created by steadfast connections called tight junctions between the endothelial cells that line its blood vessels. So effective is the barrier that most proteins and molecules cannot pass through; those that do generally require selective transport via specific receptors.

 

A similar barrier—made up of epithelial cells and tight junctions—lines the intestine and stops the trillions of microbes present in the gut from escaping into the body. It’s known that the gut bacteria themselves control integrity of this intestinal barrier, said Sven Pettersson of the Karolinska Institute in Sweden who led the new study.

 

It’s also known, he said, “that [gut] microbes could modulate brain function and development.” Pettersson and his colleagues therefore wondered whether the effect of gut microbes on the brain might be manifested in part by control of the BBB.

 

The team compared development of the BBB between germ-free fetal mice and those with normal microbiomes. As expected, the mice with normal microbiomes exhibited normal closure of the BBB toward the late stages of fetal development—a traceable antibody that could be detected readily entering the brain in the early fetus became restricted to blood vessels later on. In the fetuses whose mothers were germ-free, however, the antibody continued to enter brain tissue even late in pregnancy.

 

This increased barrier permeability was associated with low expression and disorganization of tight junction proteins and was shown by additional methods to persist into adult life. That is, pups that were born to germ-free mothers and that remained germ-free throughout life had leakier BBBs as adults.

 

“The interesting thing here is that it is [controlled by] the mother’s microbiome,” said John Cryan, chair of anatomy and neuroscience at University College Cork in Ireland. “We largely think of the influence of the microbiome as having a postnatal effect, but here they show clearly that even before the animals get exposed to microbes, the fact that their mothers are germ-free is already impacting on their development,” he said.

 

In the adult mice, transplantation of fecal matter from animals with normal microbiomes into the germ-free animals, not only corrected the expression of BBB tight junction proteins but reduced barrier permeability, the team showed. A similar effect was obtained by giving the germ-free mice bacteria-derived short chain fatty acids, suggesting that the production of metabolites may be part of the mechanism by which the bacteria control barrier integrity.

 

Although the precise mechanisms remain to be determined, said Cryan, “we know that the microbiota is critical for the developing brain and now we know it is also critical for the blood-brain barrier.”

“Therefore,” he added, “anything that threatens the microbiota homeostasis could potentially threaten the integrity of the blood-brain barrier.”

 

Indeed, “anything that happens to the mother during pregnancy that can have a negative effect on her intestinal bacteria could adversely affect the development of the fetal brain,” speculated Stephen Collins, director of the Farncombe Family Digestive Health Research Institute at McMaster University in Ontario. “For example, antibiotic usage during pregnancy theoretically—if these results can be extrapolated to humans—could actually have some impact on brain development.”

 

And that’s not all. “The development and final closure of the blood-brain barrier isn’t quite finished at birth,” added Collins, explaining that the process continues during the early days of postnatal life. “So, again, anything that interferes with intestinal bacteria . . . after the child has been born”—such as antibiotic use or delivery by cesarean section, which is thought to prevent the offspring receiving a dose of microbes from the mother’s birth canal—“could also prevent the proper closure of that barrier and therefore the proper development of the brain,” he said.

 

Collins pointed out, however, that “so far, this remains an important observation that has been made in a mouse system and hasn’t yet been proven to be the case in man.” Moreover, “there are situations in pregnancy and around birth where antibiotics are required to save the life of the mother or the fetus,” he added.

 

V. Braniste et al., “The gut microbiota influences blood-brain barrier permeability in mice,” Science Translational Medicine, 6:263ra158, 2014.

Tags

neuroscience, microbiome, disease/medicine, developmental biology and blood-brain barrier

 

By Ruth Williams | November 19, 2014

 

The Scientist » News & Opinion » Daily News

 

 

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Cystic fibrosis genetics: from molecular understanding to clinical application

Abstract

The availability of the human genome sequence and tools for interrogating individual genomes provide an unprecedented opportunity to apply genetics to medicine. Mendelian conditions, which are caused by dysfunction of a single gene, offer powerful examples that illustrate how genetics can provide insights into disease. Cystic fibrosis, one of the more common lethal autosomal recessive Mendelian disorders, is presented here as an example. Recent progress in elucidating disease mechanism and causes of phenotypic variation, as well as in the development of treatments, demonstrates that genetics continues to play an important part in cystic fibrosis research 25 years after the discovery of the disease-causing gene.

Key points

• Investigation of disease-causing variants such as F508del is resolving the mechanisms underlying cystic fibrosis transmembrane conductance regulator (CFTR) folding and will inform rational design of compounds to correct the folding of mutant CFTR.
• New tissue culture methods will facilitate the evaluation of molecular targeted therapy for a wide array of CFTR genotypes, and new animal models should enable assessment of treatment at the earliest stages of the disease.
• Analyses of affected twin and sibling pairs have quantified the contribution of genetic and non-genetic modifiers to variation in key features of cystic fibrosis.
• Candidate and genome-wide approaches have identified biologically plausible gene modifiers of lung disease severity, neonatal intestinal obstruction and diabetes in cystic fibrosis.
• Annotation of variants in CFTR will increase the utility of genetic testing in newborn screening, carrier testing and diagnostic settings. Assignment of variants as disease-causing will validate efforts to target variants for molecular therapies.
• Small-molecule therapy for cystic fibrosis has been successful for patients carrying a subset of CFTR variants. Grouping of variants according to responses in cell-based assays (that is, theratypes) could expedite treatment of affected individuals with rare CFTR genotypes.

Introduction

Cystic fibrosis (OMIM 219700) is a life-limiting autosomal recessive disorder that affects ~70,000 individuals worldwide. The condition affects primarily those of European descent, although cystic fibrosis has been reported in all races and ethnicities. Abnormally viscous secretions in the airways of the lungs and in the ducts of the pancreas in individuals with cystic fibrosis cause obstructions that lead to inflammation, tissue damage and destruction of both organ systems (Fig. 1). Other organ systems containing epithelia — such as the sweat gland, biliary duct of the liver, the male reproductive tract and the intestine — are also affected. Loss of pancreatic exocrine function results in malnutrition and poor growth, which leads to death in the first decade of life for most untreated individuals. Replacement of pancreatic enzymes and intensive therapy guided by multidisciplinary teams have revolutionized the treatment of cystic fibrosis, resulting in progressive improvements in survival to a median predicted age of ~37 years for children born with cystic fibrosis today¹. Obstructive lung disease is currently the primary cause of morbidity and is responsible for ~80% of mortality².

 

Figure 1: Cardinal features of cystic fibrosis and relative contribution of genetic modifiers to variation in select cystic fibrosis traits.

       

 

A diagnosis of cystic fibrosis is based on the presence of clinical findings shown on the left, along with an elevated sweat chloride concentration (>60 mM). The degree of organ system dysfunction varies considerably among affected individuals. Genetic modifiers and non-genetic factors both contribute to airway obstruction and infection with Pseudomonas aeruginosa — two traits that define lung disease in cystic fibrosis. Cystic fibrosis transmembrane conductance regulator (CFTR) genotype is the primary determinant of the degree of pancreatic exocrine dysfunction. The presence of CFTR variants associated with severe pancreatic exocrine dysfunction is essentially a pre-requisite for the development of diabetes and intestinal obstruction. In the setting of severe endocrine dysfunction, genetic modifiers determine when, and if, diabetes occurs and whether neonatal intestinal obstruction occurs. Genetic variation plays the predominant part in nutritional status as assessed by body mass index (BMI)70.

 

Twenty-five years ago, a variant (p.Phe508del; also known as F508del in legacy nomenclature) in the cystic fibrosis transmembrane conductance regulator (CFTR) gene was found to be the most common cause of cystic fibrosis^{3, 4, 5}. Demonstration that CFTR functions as a chloride channel regulated by cyclic AMP (cAMP)-dependent phosphorylation⁶ was consistent with the ion transport disturbances documented in cystic fibrosis tissues^{7, 8}. Key insights into cystic fibrosis pathophysiology were derived from the study of CFTR mutants⁹, correlation of CFTR dysfunction with the cellular manifestations of cystic fibrosis¹⁰, and elucidation of protein partners involved in biogenesis and membrane function¹¹. Identification of disease-causing variants in CFTR contributed a tool for both the diagnosis of cystic fibrosis and the identification of cystic fibrosis carriers¹², demonstrated the degree to which CFTR dysfunction correlates with clinical features¹³, and revealed that CFTR dysfunction can create phenotypes other than cystic fibrosis¹⁴. Over the past 5 years, there has been remarkable progress in the development of small-molecule therapy targeting CFTR bearing select disease-causing variants^{15, 16}.

 

The purpose of this Review is to highlight advances over the past decade in our understanding and treatment of cystic fibrosis that were informed by genetics. Given the breadth of the cystic fibrosis field, not all of the important contributions and publications relevant to the topic can be included. Examples have been chosen to illustrate that genetics continues to have a role in the research of Mendelian disorders long after the causative variants and the responsible gene have been discovered. This Review covers new insights into the processing defect caused by the F508del variant, advances in stem cell technology that can enable testing of therapeutics for a wide range of CFTR genotypes and the development of new animal models that are informing our understanding of organ pathology in cystic fibrosis. I also summarize progress in parsing genetic and non-genetic contributions to variability in cystic fibrosis and in the identification of modifier loci. The final section describes efforts to determine the molecular and phenotypic consequences of the majority of cystic fibrosis-causing variants and to develop molecular treatments for every defect in CFTR.

 

Figure 2: Molecular consequences of variants in CFTR.

       

 

The degree to which epithelial ion transport is altered in an individual with cystic fibrosis is determined by the effect of each disease-causing variant on the quantity and the function of cystic fibrosis transmembrane conductance regulator (CFTR). The key steps of CFTR biogenesis in an epithelial cell are depicted. The membrane-spanning domains of CFTR are shown as red boxes, the two nucleotide-binding domains as yellow circles, and the regulatory domain as a blue circle. The quantity of CFTR protein in the apical cell membrane is a product of the amount of RNA transcribed, the efficiency of RNA splicing, the fraction of protein correctly folded and the stability of the protein in the membrane. The level and/or content of CFTR transcripts can be affected by disease-causing variants in the promoter (for example, c.−234TA (also known as −102TA in legacy nomenclature))¹⁴⁰ and splice sites (for example, c.3717 + 12191 CT (legacy 3849 + 10 kb CT))¹⁴¹, or by variants that introduce a premature termination codon (PTC) and that lead to RNA decay (for example, p.Gly542X; (legacy G542X)¹⁴². The processing of CFTR can be altered by variants that cause aberrant folding of the protein, leading to degradation (for example, p.Phe508del (legacy F508del))¹⁸, or by variants that cause reduced membrane stability as a result of increased rates of endocytosis (for example, p.Asn287Tyr (legacy N287Y))¹⁴³. The function of CFTR is dependent on activity of the ion channel and on the efficiency of conductance of ions through the channel. Disease-causing variants cause reduction in activity (for example, p.Gly551Asp (legacy G551D)¹⁴⁴ or changes in the conduction properties of the chloride channel (for example, p.Arg334Trp (legacy R334W))¹⁴⁴. cAMP, cyclic AMP; ER, endoplasmic reticulum.

 

Figure 3: Molecular treatments for cystic fibrosis.

       

 

Conclusions

The discovery of CFTR 25 years ago was a triumph for genetics and a potent demonstration of its ability to deliver the molecular culprit in a Mendelian disorder. Cystic fibrosis is now positioned to reap the dividends of personalized medicine as variant-specific therapy is deployed, and a growing understanding of the genetic and environmental modifiers of cystic fibrosis enables targeting of individual risk factors. The development of new genetic models of cystic fibrosis in pigs, ferrets, rats and zebrafish provides opportunities to investigate pathophysiology and to explore therapies at the earliest stages of disease. Newborn and population screening enables prospective management of affected individuals from birth, and genomic variation will provide information on the trajectories that individual patients are likely to follow. Genetics has played and will continue to play a key part in achieving a normal lifespan for individuals with cystic fibrosis.

 

Nature Reviews Genetics | Review

Article series: Disease mechanisms

 

Garry R. Cutting^1, 

 

Published online 18 November 2014

Corrected online 20 November 2014

 

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Scientists discover new gene for devastating form of epilepsy

Using whole genome sequencing, a large group of scientists has identified a new genetic cause of progressive myoclonus epilepsy, one of the most devastating forms of epilepsy that emerges in early childhood and can result in early death

The team found that a previously unknown mutation in a potassium ion channel gene - called KCNC1 - was present in 13% of the PME patients and 7% of patients in a secondary cohort.

 The international team - including members from the University of Helsinki in Finland and the Universities of Melbourne and South Australia - report their findings in the journal Nature Genetics.

 

Progressive myoclonus epilepsies (PME) are severe, rare forms of epilepsy and frequently arise from hereditary metabolic disorders. Their core symptoms include epileptic seizures and debilitating involuntary muscle twitching. Muscle rigidity, unsteadiness and mental deterioration are often also present.

 

For the study, the international team recruited 84 patients with PME of unknown cause and used DNA sequencing to identify potential genetic causes of the disorder.

 

Modern DNA sequencing techniques have revolutionized genetic research of rare, severe diseases. In this case, the team used the technology to sequence the protein-coding elements of the human genome.

 

They managed to identify genetic causes in nearly a third of the PME patients (26 patients, 31%).

13% of PME cases had previously unknown mutation of potassium ion channel gene

Remarkably, the team found that a previously unknown mutation in a potassium ion channel gene - called KCNC1 - was present in 11 (13%) of the 84 patients and another two (7%) patients in a secondary cohort.

 

The authors note that the mutation was a "de novo" mutation - meaning it was not inherited from the patients' biological parents.

 

"De novo" or new mutations are errors that occur in cell division or in the copying of genetic material. They emerge in a germ cell of one of the parents, or in the fertilized egg. Every person has dozens of these new mutations, but they rarely cause disease.

 

The researchers estimate that this mutation occurs in about 1 in every 5.7 million conceptions, indicating that globally, at least hundreds of PME patients could have this mutation.

 

Mutations (lightning bolts) in 13 unrelated cases hit the same DNA
nucleotide in KCNC1 gene and disrupt the function of a potassium
ion channel, which causes a severe form of epilepsy.
Image credit: Lehesjoki Lab

Corresponding author and principal investigator Professor Anna-Elina Lehesjoki, from the University of Helsinki and the Folkhälsan Institute of Genetics in Helsinki, says:

 

"The mutation site is an example of a 'mutation hotspot' of the genome - a DNA nucleotide which is more prone for alterations."

 

The KCNC1 mutation that the team identified stops a potassium ion channel in brain cells working properly. The channel - called KV3.1 - plays an important part in signal transmission in the brain.

 

Ion channels are how cells, including brain cells and muscle cells, translate their chemical messages into electrical signals.

 

The cell builds up a concentration of ions inside itself - different to the concentration in the cell's environment - and this creates a voltage difference. Then, when the time is right to send a signal, the cell opens an ion channel, and because of the voltage difference, ions travel out of the cell, embodying an electrical version of a chemical message.

 

The researchers suggest the effect of the mutation is to reduce inhibitory signals - making patients susceptible to epileptic seizures and myoclonus starting in childhood. The mutation also leads to degeneration of the cerebellum - a region of the brain that plays an important role in movement control - and subtle cognitive decline in some cases.

Drugs that restore function in this ion channel may already exist

Professor Lehesjoki says because the mutation occurs in a well-known ion channel, there is hope of developing therapy that can target this.

 

"There are anti-epileptic drugs in the market that target other similar ion channels and follow-up research aims to discover a way to rescue the function of the channel in PME patients," she adds.

 

In October 2014, Medical News Today learned how a team from Johns Hopkins University in Baltimore, MD, has discovered new clues about conditions that stem from faulty ion channels, such as cardiac arrhythmias, epilepsy and Parkinson's disease. The discovery relates to a common protein that the team says plays a different role than previously thought in the opening and closing of channels that let ions in and out of cells.

 

Written by Catharine Paddock PhD

 

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Controversial Cholesterol Drug Reduces Risk of Heart Disease

The ability of ezetimibe to combat heart disease previously was in dispute.

 

Ezetimibe reduces cholesterol absorption by

inhibiting the activity of a protein called NPC1L1,

which transports free cholesterol into cells.
Credit: National Library of Medicine

A popular but controversial cholesterol drug reduces the risk of cardiovascular events such as heart attacks and stroke, researchers say. The drug, called ezetimibe, had been shower to lower cholesterol levels, but its ability to combat heart disease was in dispute.

 

But now ezetimibe, made by Merck of Whitehouse Station, New Jersey, has been found to lower the number of cardiovascular events by 6.4% when given with another cholesterol drug. The effect is significant but small; still, some scientists say that the results affirm the ‘lower is better’ hypothesis: that reducing levels of low-density lipoprotein (LDL) cholesterol (often called ‘bad’ cholesterol) lowers the risk of cardiovascular events.

 

“The question that everyone had was, ‘Would this added lowering of LDL cholesterol translate into a real clinical benefit?’” says cardiologist Christopher Cannon of the Brigham and Women’s Hospital in Boston, Massachusetts. “The answer was yes.”

 

That finding, which Cannon presented on November 17 at the American Heart Association meeting in Chicago, Illinois, may come as a relief not only to Merck, but to other pharmaceutical companies — particularly those developing cholesterol drugs (see ‘A gene of rare effect’).

 

It is much faster and cheaper to win drug approval on the basis of lowering cholesterol than of reducing cardiovascular events. Cholesterol levels change rapidly in response to medication, and they are easy to measure. Cardiovascular events, in contrast, are relatively rare. Trials to study them must enrol thousands of people to achieve statistically significant numbers of events.

 

The trial that Cannon presented today, code-named IMPROVE-IT, enrolled more than 18,000 patients and took 9 years to complete.

 

But Harlan Krumholz, a cardiologist at Yale University in New Haven, Connecticut, warns against the assumption that lower is always better when it comes to LDL cholesterol. “I don’t think you can extrapolate from this to say that any drug that lowers cholesterol is better,” he says. “We have lots of examples where that doesn’t happen.”

 

Uncertain significance

 Ezetimibe reduces cholesterol absorption by inhibiting the activity of a protein called NPC1L1, which transports free cholesterol into cells. When combined with a statin, another cholesterol-lowering drug, ezetimibe lowers cholesterol by an extra 20% compared to the statin alone.

 

This seemed to bode well for the drug’s impact on heart health when the US Food and Drug Administration approved ezetimibe in 2002. But in 2008, researchers found that the drug had no impact on the thickness of artery walls in the neck and thigh — a measure of fatty plaque build-up. This plaque build-up is thought to contribute to heart disease by restricting blood flow.

 

The results cast doubt on the usefulness of ezetimibe and of the importance lowering cholesterol in general. Statins had been shown to reduce the risk of heart disease, but that was not true for other medications that lower LDL cholesterol — including niacin and drugs called fibrates.

 

Hopes for ezetimibe were bolstered last week when a genetic analysis of 7,364 people with heart disease and 14,728 controls found that people who had a rare mutation that inactivates the NPC1L1 protein had lower LDL cholesterol levels and a lower risk of coronary heart disease.

 

Cannon tackled the controversy by presenting data from his clinical trial, which compared about 9,000 patients receiving a statin called simvastatin to another 9,000 receiving the statin and ezetimibe. (Neither the patients nor the researchres knew which patients had been assigned which drugs.) The rate of cardiovascular events was 34.7% in patients receiving only the statin, and 32.7% in patients receiving both drugs.

 

“The study affirms the central role of intensive LDL reduction in the prevention of recurrent cardiovascular events,” says Neil Stone, a cardiologist at Northwestern University in Chicago, who was not involved with the study.

 

But Stone warns that the trial was carried out in high-risk patients, a common practice used to boost the likelihood of cardiovascular events. “The data don’t speak to the use of ezetimibe in patients with low risk,” he adds. 

 

For Krumholz, the concern is that people will become overly confident in other drugs that lower cholesterol, in the absence of data on cardiovascular events. “The problem is that drugs can have multiple effects,” he says. “You can’t know for sure what the net effect is on people without formally testing it.”

 

November 18, 2014 |By Heidi Ledford and Nature magazine | Véalo en español

 

 

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Culturing Drug-Resistant Tumors

Improved methods to grow patients’ tumor cells in a dish offer opportunities to find durable therapies.

FLICKR, ANNE WESTON, LRI, CROK. WELLCOME IMAGES

Cancers can become resistant to drugs that once seemed like they could cure a person of the disease. In the unstopping march toward personalized medicine, researchers managed to culture drug-resistant lung tumor cells to screen them for sensitivity to various therapies, finding new and sometimes surprising drug candidates.

 

“It’s a substantial step,” Jeffrey Engelman of Massachusetts General Hospital Cancer Center told Time. “Because before we just had the genetic information but we wouldn’t have the cells alive so that we could test what types of therapies might work.”

 

Engelman and his colleagues published their study in Science last week (November 13). They succeeded in growing cells taken from 20 patients’ tumors. Nature News pointed out that, in many cases, the drug screens turned up unexpected candidates. In half of the tumors, for example, a drug that inhibits a protein called SRC managed to shrink tumor growth in vitro. “There were no genetic results that would have pointed to that combination,” Engelman told Nature News.

 

Engelman’s method has yet to face a clinical challenge; patients’ therapies were not altered based on the screen. “This is really setting up the criteria for what we have to look at next,” Richard Schlegel, director of the Center for Cell Reprogramming at Georgetown University School of Medicine, told the Boston Globe. “Someone has to figure out if we grow up these cells, how many times is this going to be an adequate predictor of patient response?”

Tags

tumor, screening, drug resistance, culture and cancer

 

The Scientist » The Nutshell

By Kerry Grens | November 17, 2014

 

 

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What Is Gluten?

Is gluten bad for You?

Eating gluten, the naturally occurring proteins in wheat, barley and rye can be

life-threatening to people with celiac disease.

Credit: Viktorfischer | Dreamstime

Gluten refers to the proteins found in wheat endosperm (a type of tissue produced in seeds that's ground to make flour). Gluten both nourishes plant embryos during germination and later affects the elasticity of dough, which in turn affects the chewiness of baked wheat products.

 

Gluten is actually composed of two different proteins: gliadin (a prolamin protein) and glutenin (a glutelin protein).

 

Though "true gluten" is sometimes defined as being specific to wheat, gluten is often said to be part of other cereal grains — including rye, barley and various crossbreeds — because these grains also contain protein composites made from prolamins and glutelins.

 

Why is gluten bad?

 

Gluten isn't necessarily bad, but some people are gluten-intolerant, meaning their bodies produce an abnormal immune response when it breaks down gluten from wheat and related grains during digestion.

 

The most well-known form of gluten intolerance is celiac disease, which affects one in every 141 people in the United States, according to the National Institutes of Health. When someone with celiac disease consumes gluten, it triggers an immune response that damages their intestines, preventing them from absorbing vital nutrients. 

 

Wheat allergy is a rare type of gluten intolerance — it's a classic food allergy marked by skin, respiratory or gastrointestinal reactions to wheat allergens.

 

Recently, scientists have become aware of another potential form of intolerance called nonceliac gluten sensitivity. After consuming gluten, patients with gluten sensitivity may experience many celiac disease symptoms, such as diarrhea, fatigue and joint pain, but don't appear to have damaged intestines.

 

In cases of gluten intolerance, doctors typically recommend a gluten-free diet. Patients must avoid eating any foods and ingredients that contains gluten, including bread, beer, french fries, pasta, salad dressing, soy sauce and even some soups (unless otherwise marked as "gluten-free").

 

In recent years, many people without gluten intolerance have taken up gluten-free diets. Experts worry, however, that going on these diets without explicitly needing to could be detrimental to a person's health, as gluten-free foods are often nutrient-deficient.

 

By Joseph Castro, LiveScience Contributor   |   September 17, 2013 05:27pm ET

Follow Joseph Castro on Twitter. Follow us @livescience, Facebook & Google+.

 



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Genetics Explains Why You Drink So Much Coffee

Genes & Health

For those of you attempting to kickstart your Monday: Researchers identified eight gene variants that could explain why some people drink coffee heavily, while others abstain from the drink.

If your favorite order at Starbucks is the “red-eye,” you can thank genetics for your ability to slog down all that caffeine without the shakes.

 

In a new study, scientists identified eight genetic variants that could partly explain why some people drink coffee by the pot, while others avoid the stimulating beverage altogether. By outlining the genetic foundation for coffee consumption, scientists believe they can find firmer evidence to support the positive — and negative — health effects of the popular beverage.

Java Genes

Researchers from the Harvard School of Public Health and Brigham and Women’s Hospital investigated the genomes of 120,000 European and African American coffee drinkers along with data on how many cups a day they consumed, using findings from dozens of previous studies. Their statistical analysis revealed six new gene variants that governed coffee consumption, and reaffirmed the presence of two others previously discovered by the same group of researchers.

 

The team identified variants in or near genes that play roles in learning, caffeine metabolism, blood pressure regulation and addiction. Two newly discovered variants, near the genes BDNF and SLC6A4, reinforce the positive effects of coffee’s molecular properties. For example, BDNF is involved in the release of pleasure-inducing neurotransmitters like serotonin and dopamine.

Researchers published their findings Tuesday in the journal Molecular Psychiatry.

Heavy Drinkers

Participants in the study that inherited five or six of the gene variations were more likely to be heavy coffee drinkers — four or more cups a day — than those who inherited just one or two, the Boston Globe reports. People with more coffee gene variants may drink more because they metabolize it quickly; thus, they enjoy coffee’s stimulating effects for a shorter period of time.

 

Some of the same gene variations seen in heavy coffee drinkers are risk factors for smoking initiation and obesity. Both obesity and smoking may be fueled by addiction, which could explain why some people can’t stop at just one cup. Researchers plan to dig deeper into the genetics of coffee drinking to see how variants may be positively and negatively affecting coffee fanatics’ health.

 

In the debate about whether coffee is good or bad for your health, genetics could cut through the noise and someday offer more definitive answers.

 

By Carl Engelking | October 7, 2014 1:19 pm

Photo credit: RobinE/Shutterstock

CATEGORIZED UNDER: Living World, top posts

 

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Sealed With a Kiss

A single intimate smooch can transfer upwards of 80 million bacteria.


WIKIMEDIA, ROBERT & MIHAELA VICOL

Locking lips spreads more than just love. A healthy dose of microbes are also swapped between kissing couples, according to a study published today (November 17) in Microbe. Researchers in Amsterdam swabbed the mouths and collected saliva from 21 couples visiting a zoo in the city both before and after they shared 10-second kiss. They found that the couples tended to have similar microbes inhabiting their mouths, likely because they share kisses, food, and space on a regular basis. “Apparently, being with somebody for an extended amount of time and having a relationship leads to a similar collection of bacteria on the tongue,” Remco Kort, lead author and biologist at the Netherlands Organization for Applied Scientific Research, told Time.

 

But when the researchers had one partner sip a probiotic yogurt drink, which contains bacteria not normally present in the mouth, prior to kissing their mate again, they found that an average of 80 million bacteria were swapped between kissers. “French kissing is a great example of exposure to a gigantic number of bacteria in a short time,” Kort told BBC News. “But only some bacteria transferred from a kiss seemed to take hold on the tongue. Further research should look at the properties of the bacteria and the tongue that contribute to this sticking power.”

Tags

probiotic, mouth microbiome, microbiome, microbiology and kissing

The Scientist » The Nutshell

By Bob Grant | November 17, 2014

 

 

http://www.the-scientist.com/?articles.view/articleNo/41450/title/Sealed-With-a-Kiss/

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The science behind total recall: New player in brain function and memory

Artist's abstraction (stock illustration).

Credit: © agsandrew / Fotolia

Is it possible to change the amount of information the brain can store? Maybe, according to a new international study led by the Research Institute of the McGill University Health Centre (RI-MUHC). Their research has identified a molecule that puts a brake on brain processing and when removed, brain function and memory recall is improved. Published in the latest issue of Cell Reports, the study has implications for neurodevelopmental and neurodegenerative diseases, such as autism spectral disorders and Alzheimer's disease.

 

"Previous research has shown that production of new molecules is necessary for storing memories in the brain; if you block the production of these molecules, new memory formation does not take place," says RI-MUHC neuroscientist, Dr. Keith Murai, the study's senior author and Associate Professor in the Department of Neurology and Neurosurgery at McGill University. "Our findings show that the brain has a key protein that limits the production of molecules necessary for memory formation. When this brake-protein is suppressed, the brain is able to store more information."

 

FXR1P: a controller of certain forms of memory

 

Dr. Murai and his colleagues used a mouse model to study how changes in brain cell connections produce new memories. They demonstrated that a protein, FXR1P (Fragile X Related Protein 1), was responsible for suppressing the production of molecules required for building new memories. When FXR1P was selectively removed from certain parts of the brain, these new molecules were produced that strengthened connections between brain cells and this correlated with improved memory and recall in the mice.

 

Disease link

 

"The role of FXR1P was a surprising result," says Dr. Murai. "Previous to our work, no-one had identified a role for this regulator in the brain. Our findings have provided fundamental knowledge about how the brain processes information. We've identified a new pathway that directly regulates how information is handled and this could have relevance for understanding and treating brain diseases."

 

"Future research in this area could be very interesting," he adds. "If we can identify compounds that control the braking potential of FXR1P, we may be able to alter the amount of brain activity or plasticity. For example, in autism, one may want to decrease certain brain activity and in Alzheimer's disease, we may want to enhance the activity. By manipulating FXR1P, we may eventually be able to adjust memory formation and retrieval, thus improving the quality of life of people suffering from brain diseases."

 

Date:November 13, 2014

Source:McGill University Health Centre

 

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