SorLA Controls Neurotrophic Activity by Sorting of GDNF and Its Receptors GFR alpha 1 and RET

Peer reviewe

Thirty-five common variants for coronary artery disease: the fruits of much collaborative labour

Coronary artery disease (CAD) is the leading cause of death worldwide. Affected individuals cluster in families in patterns that reflect the sharing of numerous susceptibility genes. Genome-wide and large-scale gene-centric genotyping studies that involve tens of thousands of cases and controls have now mapped common disease variants to 34 distinct loci. Some coronary disease common variants show allelic heterogeneity or copy number variation. Some of the loci include candidate genes that imply conventional or emerging risk factor-mediated mechanisms of disease pathogenesis. Quantitative trait loci associations with risk factors have been informative in Mendelian randomization studies as well as fine-mapping of causative variants. But, for most loci, plausible mechanistic links are uncertain or obscure at present but provide potentially novel directions for research into this disease's pathogenesis. The common variants explain ∼4% of inter-individual variation in disease risk and no more than 13% of the total heritability of coronary disease. Although many CAD genes are presently undiscovered, it is likely that larger collaborative genome-wide association studies will map further common/low-penetrance variants and hoped that low-frequency or rare high-penetrance variants will also be identified in medical resequencing experiments

Genome-Wide Association Studies in Atherosclerosis

Cardiovascular disease remains the major cause of worldwide morbidity and mortality. Its pathophysiology is complex and multifactorial. Because the phenotype of cardiovascular disease often shows a marked heritable pattern, it is likely that genetic factors play an important role. In recent years, large genome-wide association studies have been conducted to decipher the molecular mechanisms underlying this heritable and prevalent phenotype. The emphasis of this review is on the recently identified 17 susceptibility loci for coronary artery disease. Implications of their discovery for biology and clinical medicine are discussed. A description of the landscape of human genetics in the near future in the context of next-generation sequence technologies is provided at the conclusion of this review

Camostat mesylate inhibits SARS-CoV-2 activation by TMPRSS2-related proteases and its metabolite GBPA exerts antiviral activity.

BACKGROUND: Antivirals are needed to combat the COVID-19 pandemic, which is caused by SARS-CoV-2. The clinically-proven protease inhibitor Camostat mesylate inhibits SARS-CoV-2 infection by blocking the virus-activating host cell protease TMPRSS2. However, antiviral activity of Camostat mesylate metabolites and potential viral resistance have not been analyzed. Moreover, antiviral activity of Camostat mesylate in human lung tissue remains to be demonstrated. METHODS: We used recombinant TMPRSS2, reporter particles bearing the spike protein of SARS-CoV-2 or authentic SARS-CoV-2 to assess inhibition of TMPRSS2 and viral entry, respectively, by Camostat mesylate and its metabolite GBPA. FINDINGS: We show that several TMPRSS2-related proteases activate SARS-CoV-2 and that two, TMPRSS11D and TMPRSS13, are robustly expressed in the upper respiratory tract. However, entry mediated by these proteases was blocked by Camostat mesylate. The Camostat metabolite GBPA inhibited recombinant TMPRSS2 with reduced efficiency as compared to Camostat mesylate. In contrast, both inhibitors exhibited similar antiviral activity and this correlated with the rapid conversion of Camostat mesylate into GBPA in the presence of serum. Finally, Camostat mesylate and GBPA blocked SARS-CoV-2 spread in human lung tissue ex vivo and the related protease inhibitor Nafamostat mesylate exerted augmented antiviral activity. INTERPRETATION: Our results suggest that SARS-CoV-2 can use TMPRSS2 and closely related proteases for spread in the upper respiratory tract and that spread in the human lung can be blocked by Camostat mesylate and its metabolite GBPA. FUNDING: NIH, Damon Runyon Foundation, ACS, NYCT, DFG, EU, Berlin Mathematics center MATH+, BMBF, Lower Saxony, Lundbeck Foundation, Novo Nordisk Foundation

Sortilins: new players in lipoprotein metabolism

PURPOSE OF REVIEW: Sortilins are sorting receptors that direct proteins through secretory and endocytic pathways of the cell. Previously, these receptors have been shown to play important roles in regulating protein transport in neurons and to control neuronal viability and death in many diseases of the nervous system. Recent data, including genome-wide association studies, now suggest equally important functions for sortilins in control of systemic lipoprotein metabolism and risk of cardiovascular disease. This review discusses the evidence implicating two members of this gene family, sortilin and SORLA, in cardiovascular processes. RECENT FINDINGS: SORLA is a multifunctional receptor expressed in macrophages and vascular smooth muscle cells. It may act proatherogenic by promoting intimal SMC migration and by regulating apolipoprotein A-V dependent activation of lipoprotein lipase to modulate systemic triglyceride levels. Sortilin, encoded by the cardiovascular risk locus 1p13.3, is a novel regulator of hepatic lipoprotein production. It interacts with apolipoprotein B-100 to control release of very low-density lipoproteins, thereby affecting plasma cholesterol concentrations. SUMMARY: Recent data shed light on the importance of sorting receptors in control of cellular and systemic lipoprotein metabolism and how altered trafficking pathways may represent a major risk factor for dyslipidemia and atherosclerosis in the human population

Genome-wide identification of Wnt/β-catenin transcriptional targets during Xenopus gastrulation

The canonical Wnt/β-catenin signaling pathway plays multiple roles during Xenopus gastrulation, including posteriorization of the neural plate, patterning of the mesoderm, and induction of the neural crest. Wnt signaling stabilizes β-catenin, which then activates target genes. However, few targets of this signaling pathway that mediate early developmental processes are known. Here we sought to identify transcriptional targets of the Wnt/β-catenin signaling pathway using a genome-wide approach. We selected putative targets using the criteria of reduced expression upon zygotic Wnt knockdown, β-catenin binding within 50kb of the gene, and expression in tissues that receive Wnt signaling. Using these criteria, we found 21 novel direct transcriptional targets of Wnt/β-catenin signaling during gastrulation and in addition have identified putative regulatory elements for further characterization in future studies

Noggin Is Required For First Pharyngeal Arch Differentiation In The Frog Xenopus Tropicalis

The dorsal ventral axis of vertebrates requires high BMP activity for ventral development and inhibition of BMP activity for dorsal development. Presumptive dorsal regions of the embryo are protected from the ventralizing activity of BMPs by the secretion of BMP antagonists from the mesoderm. Noggin, one such antagonist, binds BMP ligands and prevents them from binding their receptors, however, a unique role for Noggin in amphibian development has remained unclear. Previously, we used zinc-finger nucleases to mutagenize the noggin locus in Xenopus tropicalis. Here, we report on the phenotype of noggin mutant frogs as a result of breeding null mutations to homozygosity. Early homozygous noggin mutant embryos are indistinguishable from wildtype siblings, with normal neural induction and neural tube closure. However, in late tadpole stages mutants present severe ventral craniofacial defects, notably a fusion of Meckel\u27s cartilage to the palatoquadrate cartilage. Consistent with a noggin loss-of-function, mutants show expansions of BMP target gene expression and the mutant phenotype can be rescued with transient BMP inhibition. These results demonstrate that in amphibians, Noggin is dispensable for early embryonic patterning but is critical for cranial skeletogenesis