Lifespan synaptic atlas gives developmental insights
Scientists at the University of Edinburgh have comprehensively mapped synaptic connections of the mouse brain at different ages, gaining new insights into how synaptic connectivity changes over the lifespan. The team imaged the synaptic connections of mice at 10 different ages, ranging from 1 day to 18 months. They showed that synapse diversity increased until early adulthood, leading to differentiation of brain regions. Brain regions remained differentiated through midlife, then dedifferentiated, accompanied by enlargement of individual synapses. The authors concluded that changes in synaptic brain architecture “potentially accounts for lifespan transitions in intellectual ability, memory, and susceptibility to behavioral disorders.” The paper was published in the June 12, 2020, issue of Science.
Prozac for infectious disease
Researchers at the University of Texas Southwestern Medical Center have demonstrated that gut serotonin loads affected bacterial virulence in a mouse model of infections with enterohemorrhagic Escherichia coli (EHEC), which can cause serious gastrointestinal disease and even death, and Citrobacter rodentium, the mouse equivalent of EHEC infections. The team showed that bacteria were able to sense serotonin levels via their membrane kinase CpxA, and that high serotonin levels inhibited the production and secretion of virulence factors. Increasing serotonin levels in the gut, either through genetic knockout of the serotonin transporter or through the serotonin-targeting antidepressant Prozac (fluoxetine, Eli Lilly and Co.) decreased bacterial loads and increased survival when mice were infected with C. rodentium. “The fact that one can conceptually co-opt… drugs already used in the clinic (e.g., Prozac) to treat infectious diseases is potentially exciting,” the authors wrote. “Importantly, these inter-kingdom signaling systems that engage neurotransmitters may not be restricted to impacting the pathogenesis of EHEC and C. rodentium. Many GI pathogens, such as Salmonella, Yersinia enterocolytica, Shigella disenteria, and others, encode the CpxA serotonin/indole receptor.” They reported their findings in the June 9, 2020, online issue of Cell Host & Microbe.
How CDK comes unglued
Investigators at the Friedrich Miescher Institute for Biomedical Research and the Dana-Farber Cancer Institute have identified a new “molecular glue” that can direct ubiquitin ligases to proteins. Targeted degradation via the redirection of ubiquitin ligase activity is behind the anticancer activity of thalidomide and its peers, and is seen as a promising strategy to target currently undruggable classes of proteins such as transcription factors. The authors screened for cytotoxicity and expression levels of ubiquitin E3 ligase in response to about 4,500 compounds across several hundred cell lines, and showed that the cyclin-dependent kinase (CDK) inhibitor CR8 acts by inducing ubiquitination and degradation of its target kinase. Unlike other molecular glues, CR8 did not have a binding pocket for its substrate, but worked by surface binding. “Our studies demonstrate that chemical alteration of surface-exposed moieties can confer gain-of-function glue properties to an inhibitor, and we propose this as a broader strategy through which target-binding molecules could be converted into molecular glues,” the authors wrote. They published their findings in the June 4, 2020, issue of Nature.
Macrophages rewire cholesterol metabolism for bacterial toxin defense
Scientists at the University of California, Los Angeles, have identified the mechanism that macrophages and neutrophils use to block bacteria from a class of bacterial toxins, the cholesterol-dependent cytolysins (CDCs). CDCs are bacterial toxins that bind to membrane cholesterol and induce the formation of pores, killing target cells by leaving their membranes leaky. Known defense strategies of other cell types would compromise the ability of macrophages and neutrophils to eat bacteria, prompting the authors to investigate whether those cells have evolved unique defense strategies. They found that macrophages and neutrophils rewired cholesterol metabolism in response to interferon (IFN) signaling, producing the oxysterol 25-hydroxycholesterol, which rendered them resistant to CDCs. “Blocking the ability of IFN to reprogram cholesterol metabolism abrogates cellular protection and renders mice more susceptible to CDC-induced tissue damage,” the authors wrote. “These studies illuminate targeted regulation of membrane cholesterol content as a host defense strategy.” Their work appeared in the June 8, 2020, online issue of Nature Immunology.
ApoE4’s role in Alzheimer’s blood vessels
The vast majority of Alzheimer’s disease (AD) patients have amyloid deposits in the blood vessels of the brain that damage blood-brain barrier (BBB) function and play a role in cognitive decline. Like for AD itself, the ApoE4 variant is a genetic risk factor for that cerebral amyloid angiopathy (CAA). Researchers from the Massachusetts Institute of Technology (MIT) have shown that ApoE4 increased the risk of CAA through its effects on calcineurin-nuclear factor of activated T cells (calcineurin-NFAT) signaling. In an iPSC-derived model of the BBB, ApoE4-derived cells led to greater accumulation of amyloid beta in the BBB organoid, and that deregulated calcineurin-NFAT signaling. The authors concluded that “our study reveals the role of pericytes in APOE4-mediated CAA and highlights calcineurin-NFAT signaling as a therapeutic target in CAA and Alzheimer’s disease.” They published their results in the June 8, 2020, online issue of Nature Medicine.
HRAS-driven translation helps skin prevent tumors
Given the amount of mutagenic damage it typically sustains, skin is surprisingly resistant to developing cancer. Now, researchers at Fred Hutchinson Cancer Research Center have identified a surprising factor that helps skin tissue suppress the growth of mutant clones – oncogenic HRAS. They showed that the transcription of oncogenic HRAS set off changes that led to the loss of progenitor cell self-renewal capacity. They also showed that those changes were implemented by the ubiquitin ligase FBXO32, which “specifically inhibits epidermal renewal without affecting overall proliferation, thus restraining HRAS-driven tumorigenesis while maintaining normal tissue growth. Thus, oncogene-driven translation is not necessarily inherently tumor promoting but instead can manage widespread oncogenic stress by steering progenitor fate to prolong normal tissue growth,” the authors wrote. They reported their findings in the June 8, 2020, online issue of Cell Stem Cell.
Discovering pharmacological enzyme activators
Although there are some examples of enzyme activators, most pharmacological research has focused on inhibition. Now, scientists at the Scripps Research Institute have adapted the screening method, activity-based protein profiling (ABPP), to identify activators rather than inhibitors of enzyme activity. They then used ABPP to identify an activator of the LYPLAL1, whose functions are poorly characterized, though it has been linked to multiple metabolic disorders in genomewide association studies. The researchers showed that the activator increased insulin sensitivity and glucose tolerance in insulin-resistant mice. The authors concluded that “these findings reveal a new mode of pharmacological regulation for this large enzyme family and suggest that ABPP may aid discovery of activators for additional enzyme classes.” Their work appeared in the June 8, 2020, online issue of Nature Chemical Biology.
Broad-spectrum antiviral has activity against Zika
Researchers from Beth Israel Deaconess Medical Center have reported on a broad-spectrum antiviral that was effective at reducing blood Zika virus levels, and in some cases preventing blood Zika infections, when given after subcutaneous or vaginal exposure to Zika. The drug, galidesivir, also reduced viral levels in neural tissues. Zika virus infections are usually harmless, but infection in pregnant women can result in severe neurological damage to their fetuses. Galidesivir is a direct-acting antiviral originally identified for its activity against filoviruses such as Marburg virus, but further testing has shown that the compound, which is in phase I trials for Marburg virus, yellow fever and SARS-CoV-2 infections, has broad-spectrum antiviral activity. The team reported that the compound was effective at reducing viral levels, and did not show teratogenic effects at any dose tested. They concluded that “the antiviral efficacy of galidesivir observed in the blood and central nervous system of infected animals warrants continued evaluation of this compound for the treatment of flaviviral infections.” They published their work in the June 10, 2020, issue of Science Translational Medicine.
NETS and mets
A study by scientists at Sun Yat-Sen University has been the first to show that neutrophil extracellular traps (NETs) are elevated in liver metastases of breast and colon cancer patients, while serum NET levels can predict liver metastases in patients with early stage breast cancer. The study also found that the extracellular DNA sensor, coiled-coil domain containing protein-25 (CCDC25), represents a promising potential new therapeutic target for preventing cancer metastasis, which is particularly problematic in breast cancer. NETs are released by neutrophils in order to trap microorganisms during infection. Recent studies have indicated that NETs are associated with cancer metastasis in mice, but whether they are present in human cancers remains largely unknown, as do any possible functional role or clinical importance in metastasis. Because NETs trap microorganisms, any pro-metastatic effects have been proposed to involve physically trapping disseminating cancer cells, with recent studies also having suggested that NET-DNA is associated with cancer metastasis in mouse models. However, the functional role and clinical importance of NET-DNA in metastasis in patients with cancer are unclear, as are details of any interaction between NETs and cancer cells. The researchers showed that while NETs were scarce in primary tumors, they were readily detectable in various metastases, with liver metastases showing the most abundant NET infiltration. In early stage breast cancer patients, higher serum MPO-DNA levels were shown to be an independent variable associated with subsequent metastasis to the liver, but not to other organs. The team published its findings in the June 11, 2020, issue of Nature.