Microbiome changes precede tumor development in CRC

Researchers at the Harvard T.H. Chan School of Public Health, Memorial Sloan-Kettering Cancer Center and Massachusetts General Hospital have analyzed the fecal and mucosal microbiome of individuals with Lynch syndrome, and they used their findings to identify microbiome members that could play a causal role in the development of colorectal cancer (CRC). Microbiome composition is altered in CRC patients, but defining whether the microbiome alters cancer risk or cancer alters the microbiome has been challenging. Lynch syndrome is a hereditary syndrome that puts individuals at very high risk of developing CRC, and accounts for about one in 30 CRC cases overall. The team looked at the microbiome in Lynch syndrome patients prior to and after the development of CRC, and identified several microbiome changes that preceded tumor development, although such changes were only weakly predictive of how long it would take patients to develop precancerous adenomas. The authors concluded that their work “suggests that the effectiveness of prospective microbiome monitoring for adenomas may be limited but supports the potential causality of these consistent, early microbial changes in colonic neoplasia.” They reported their findings in the April 1, 2020, issue of Cell Host & Microbe.

Converting catch and release to PARP traps

PARP inhibitors, as a class, are somewhat misnamed. Although they were indeed developed for their ability to inhibit the DNA repair enzyme poly(ADP-ribose) polymerase-1 (PARP-1), their clinical efficacy has turned out to hinge on their ability to trap PARP-1 at the site of the DNA break. Investigators at the University of Montreal and the University of Pennsylvania School of Medicine have identified structural aspects of PARP inhibitors that affected their propensity to trap PARP-1, and structural alterations that could convert a PARP inhibitor into a trapping compound, increasing its ability to kill cancer cells. “These developments are pertinent to clinical applications where PARP-1 trapping is either desirable or undesirable,” the authors wrote. Their work appeared in the April 3, 2020, issue of Science.

Smart bacterium senses environment

Scientists at the Massachusetts Institute of Technology have engineered the gut bacterium Bacteroides thetaiotaomicron with a logic circuit that enabled the bacterium to sense its environment and respond to changes in environment with changes in behavior. Gut microbes naturally produce a very large number of metabolites that affect gut health, and have been programmed in preclinical experiments to produce therapeutically useful molecules. Ideally, a bacterium could be programmed to sense its environment and produce therapeutics on an as-needed basis. The authors constructed a logic circuit that allowed B. thetaiotaomicron to distinguish between environments associated with its production in a fermentation vat, the gut, and the environment after release. “This circuit was found to be stable under laboratory conditions for at least 12 days and to function in bacteria associated with a primary colonic epithelial monolayer in an in vitro human gut model system,” the authors wrote. “Our human gastrointestinal model was able to rapidly evaluate the multiple states of the circuit, but this came at the cost of being able to study the circuit response for only [eight hours], after which bacterial overgrowth compromised the monolayer. More detailed microphysiological systems could be used to evaluate circuits for up to weeks.” They reported their results in the March 30, 2020, online issue of Nature Biotechnology.

The dose makes the poison – timing, too

A team at ETH Zurich has unraveled the molecular details that determine whether prostaglandins will have proinflammatory or anti-inflammatory effects. They showed that cyclopentenone-containing prostaglandins and structurally related oxidized phospholipid species were anti-inflammatory at low doses, and when they were released before Toll-like receptor (TLR) activation. In contrast, higher doses, even below the threshold for toxicity, led to a proinflammatory response and apoptosis. “These results uncover unexpected pro- and anti-inflammatory activities of physiologically relevant lipid species generated by enzymatic and non-enzymatic oxidation dependent on their concentration, a phenomenon known as hormesis,” the authors wrote. “These findings better clarify the controversial role of oxidized phospholipids in inflammation.” The scientists published their findings in the March 30, 2020, issue of Cell Reports.

Minimal phenotyping gives minimal insights into MDD genetics

Researchers from the Major Depressive Disorder (MDD) Working Group of the Psychiatric Genomics Consortium have analyzed the utility of so-called minimal phenotyping for identifying genetic risk loci for MDD, and have come to the conclusion that the method may muddy the waters rather than clarify genetic loci. Genomewide association studies (GWAS) require large sample sizes, and accurate medical diagnoses of large caseloads make GWAS for psychiatric diseases costly. Minimal phenotyping, which relies on one or a few symptoms instead of a full clinical workup to diagnose a disorder, has been used as an alternative in some studies. However, the consortium looked at such studies and found that diagnosis of MDD via minimal phenotyping was often inaccurate, as symptoms are heterogenous, antidepressants are prescribed for other illnesses as well, and MDD is often co-morbid with other diseases. In their analysis, the authors showed that “GWAS based on minimal phenotyping definitions preferentially identifies loci that are not specific to MDD, and, although it generates highly predictive polygenic risk scores, the predictive power can be explained entirely by large sample sizes rather than by specificity for MDD. Our results show that reliance on results from minimal phenotyping may bias views of the genetic architecture of MDD and impede the ability to identify pathways specific to MDD.” The team reported its work in the March 30, 2020, online issue of Nature Genetics.

At the largest zebrafish facility in the country, Kevin Bishop, NHGRI Zebrafish Core staff member, holds up a tank of zebrafish to observe their behavior and physiology. Credit: Ernesto del Aguila III, National Human Genome Research Institute, NIH

Hypoxia linked to common form of muscular dystrophy

Facioscapulohumeral muscular dystrophy (FSHD) is the most common autosomal dominant form of muscular dystrophy. FSHD has an adult onset with a frequency of one in 8,000 Individuals. Previous work had identified inappropriate reactivation of DUX4 in adulthood as a cause of FSHD, but because DUX4 is a transcription factor, its identification had not led to clear insights into the critical molecular pathways that led from DUX4 reactivation to FSHD. The researchers used CRISPR experiments in zebrafish to identify genes that were affected by DUX4 re-expression. Pathway analysis of DUX4-activation revealed alterations in hypoxia signaling pathways, and when cells expressed DUX4, the cell oxygen levels within the cell decreased. FDA-approved drugs that could prevent DUX4-mediated cell death were identified in the study, including mTOR inhibitor rapamycin. Beyond the identification of compounds with potential therapeutic benefit for FSHD, “our experimental approach presents an accelerated paradigm toward mechanistic understanding and therapeutic discovery of a complex genetic disease, which may be translatable to other diseases with well-established phenotypic selection assays,” the authors wrote. The team reported its findings in the March 25, 2020, issue of Science Translational Medicine.

Stopping tau in its tracks

Investigators at the University of California at Santa Barbara have identified the low-density lipoprotein receptor-related protein 1 (LRP1) as a key to controlling the internalization and spread of tau protein in Alzheimer’s disease (AD). Tau aggregates are a critical feature of advanced AD, and once tau aggregation has begun, the protein can travel from neuron to neuron in a prion-like fashion. The authors used CRISPR to knock down various members of the low-density lipoprotein receptor (LDLR) family, as previous work had shown that proteins that interact with LDLRs were important for the spread of tau. They showed that LRP1 took up both tau oligomers and fibrils via endocytosis. “Our results identify LRP1 as a key regulator of tau spread in the brain, and therefore a potential target for the treatment of diseases that involve tau spread and aggregation,” the authors wrote. They published their study in the April 2, 2020, issue of Nature.

Optogenetic plaque model traces neurodegeneration in AD

Researchers at Yale-NUS have developed an optogenetic model that enabled them to separate different effects of intracellular amyloid beta oligomers from each other. As plaque-targeting approaches have failed over and over to make a difference in late-stage clinical trials for AD, attention has turned to other forms of amyloid beta, most notably oligomers. However, oligomers have been more challenging to study. By using optogenetics to induce rapid oligomerization, the researchers demonstrated that both the expression and induced oligomerization of amyloid beta were detrimental to longevity and health. However, oligomerization was far worse, leading to a rapid decline and death. Neuronal expression without light showed a mean survival of approximately 57 days, while those exposed to light lived around 18 days. Lithium treatment could partially reverse the damage. The authors noted that they “present the first model to separate different aspects of disease progression.” They reported their findings in the March 31, 2020, edition of eLife.

Once repulsive, always repulsive

Investigators at Osaka University have shown that the developmental protein repulsive guidance molecule A (RGMa) regulates neuronal differentiation and survival during brain development. In the adult central nervous system, RGMa is considered a negative factor for neuronal recovery in neurodegenerative disorders and injuries, but its precise function in the normal adult brain remained unknown. The researchers demonstrated that RGMa was expressed in the adult hippocampus and provided evidence that RGMa signaling suppressed adult neurogenesis in mice. Knockdown of RGMa increased survival of newborn neurons in the hippocampus, though they did not integrate into neuronal circuits properly. The authors concluded that “these findings present a function for RGMa in the adult brain and add to the intricate molecular network that regulates adult brain plasticity.” Their paper appeared in the April 2, 2020, issue of Stem Cell Reports.

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