Serine improves memory in Alzheimer’s mouse model

Researchers at the French INSERM and the Commissariat for Atomic and Alternative Energies have linked defects in glucose metabolism early in Alzheimer’s disease (AD) to later synaptic dysfunction and memory deficits. Impaired glucose metabolism has been detected long before the onset of clinical disease in both mouse models and AD patients, but whether such early hypometabolism is relevant to clinical disease had not been worked out. The authors demonstrated that impaired glucose metabolism by astrocytes, one of the major classes of glial cells in the brain, led to deficits in serine metabolism. The D-serine enantiomer is a co-agonist of the NMDA receptor, whose activation is a molecular mechanism of learning and information storage. The authors demonstrated that serine supplementation beginning in mouse early middle age reduced learning deficits in a mouse model of AD. They concluded that “astrocytic glycolysis controls cognitive functions and suggest oral L-serine as a ready-to-use therapy for AD.” Additionally, “understanding this metabolic pathway and its link to brain function may hold promise for the future treatment of other types of neurodegeneration characterized by early hypometabolism like Parkinson’s and Huntington’s.” Their work appeared in the March 5, 2020, issue of Cell Metabolism.

From junk to noncoding to coding

Investigators at the University of California at San Francisco have demonstrated the existence of hundreds of what they termed microproteins, which are shorter than classical proteins and translated from start sites that are not classical AUG start codons. Ideas of the genome have progressed from DNA sequences that either code for proteins or are so-called “junk” sequences of no biological value, to a minority of coding sequences and many noncoding regions that perform regulatory functions, plus maybe some junk. However, some recent studies have shown that proteins can start from places other than canonical AUG “start” codons, and amino acids too short to be considered classical proteins could have biological roles within cells. The authors used a combination of CRISPR editing and ribosomal profiling to identify “multiple microproteins encoded in upstream open reading frames, which form stable complexes with the main, canonical protein encoded on the same messenger RNA... Together, our results point to a family of functional human microproteins that play critical and diverse cellular roles.” They reported their discovery in the March 6, 2020, issue of Science.

Keeping stem cells quiescent enables greater ultimate potency

Researchers at the Mount Sinai School of Medicine have demonstrated that quiescent hematopoietic stem cells (HSCs) were characterized by repressed lysosome activity, and that repressing lysosomal activity pharmacologically maintained stem cell quiescence and potency in cell culture. HSC transplantation can cure some blood diseases, but maintaining stem cells in culture so that they retain their potency has been challenging. In their work, the team showed that repressing lysosomal activity maintained cultured stem cells in a quiescent state. Once such cells were primed, they were much more potent and able to divide. The researchers concluded that “our work illuminates several key concepts regarding HSC quiescence and potency. Specifically, the lysosomal regulation of HSC activity may be further explored for therapeutic purposes.” They reported their findings in the Feb. 27, 2020, online issue of Cell Stem Cell.

Female, male fat tissue flight inflammation differently

Researchers at the University of Melbourne have discovered that fat tissue that surrounds the viscera (visceral adipose tissue, VAT) had different ways of limiting inflammation in male and female mice. Adipose tissue functions as both an energy store and an endocrine organ, and VAT is particularly important for the regulation of systemic metabolism. Impaired VAT function, such as in obesity, is associated with insulin resistance and type 2 diabetes mellitus. In their work, the team showed that male mice had higher levels of regulatory T cells in their VAT, and that “those cells were markedly different from their female counterparts in phenotype, transcriptional landscape and chromatin accessibility,” the authors wrote. Specifically, “in females, inflammation is limited by estrogen. In males, however, increased VAT inflammation and male-specific IL-33-producing stromal cells mediate the active recruitment and local expansion of Treg cell numbers… Overall, we find that sex-specific differences in Treg cells from VAT are determined by the tissue niche in a sex-hormone-dependent manner to limit adipose tissue inflammation.” They published their findings in the Feb. 26, 2020, issue of Nature.

BioPROTACs cut out middleman, and small molecule

Researchers at Merck & Co. Inc. have systematically explored a new targeting approach related to proteolytic targeting chimeras (PROTACs) and immunomodulatory (IMiD) drugs, both of which induce the destruction of their target proteins via the ubiquitin-proteasome system rather than inhibiting it via a small-molecule or biologic drug. IMiD drugs such as Thalomid (thalidomide, Celgene Corp.) and related molecules are approved for the treatment of multiple myeloma, while the first PROTACs entered clinical trials in 2019. PROTACs, which consist of a small molecule for targeting, a ubiquitin ligase to tag the target for destruction and a linker between the two, look to be a powerful new approach to drugging targets that are not easily inhibited. However, so far only a few ubiquitin ligases have proved amenable to the development of PROTACs. The authors showed that by replacing the small molecule and linker with the direct engineering of a targeting peptide into a ubiquitin ligase, engineering what they called a bioPROTAC, they were able to achieve degradation of target proteins with eight out of 10 ligases they tested. “Although bioPROTACs are not novel entities, the work described [by us represents] a systematic exploration of this approach,” the authors wrote. BioPROTACS “can be used as powerful tools for uncovering biology, informing on the design of small molecule target degraders (e.g. PROTACs), and, if delivery issues can be addressed, potential therapeutics.” They reported their findings in the March 2, 2020, online issue of the Proceedings of the National Academy of Sciences.

‘Gut bug’ has intratumoral effects

The microbiome affects antitumor immunity, but to date, research into how it does so has focused on the activation of immunity in the gut. Now, scientists at the University of Chicago and the University of Texas Southwestern Medical Center have shown that in mouse models, systemic administration of the commensal gut bacterium Bifidobacterium also affected antitumor immunity by accumulating in the tumor microenvironment, where it potentiated the effects of CD47 blockade. CD47 is a checkpoint molecule that fulfills an analogous function to the T-cell checkpoint molecule PD-1 on dendritic cells of the innate immune system. The authors showed that intratumoral Bifidobacterium activated innate immune cells via the interferon pathway, and those activated cells could be kept active by blocking CD47 signaling. Their work appeared in the March 6, 2020, online issue of the Journal of Experimental Medicine.

Decoy exosomes fight bacterial toxin

Scientists at New York University have discovered that the protein ATG16L1, known for its involvement in autophagy, played a role in host defense that was independent of autophagy and protein degradation. Multiple bacteria produce pore-forming toxins that insert themselves into host cell membranes, including some strains of methicillin-resistant Staphylococcus aureus (MRSA), which produce alpha-toxin. In their work, the team showed that one function of ATG16L1 was to aid in the formation of exosomes that were released into the bloodstream and acted as a form of decoy, soaking up alpha-toxin release by MRSA. The authors concluded that “ATG proteins mediate a previously unknown form of defense in response to infection, facilitating the release of exosomes that serve as decoys for bacterially produced toxins.” They published their findings in the Feb. 5, 2020, issue of Nature.

Unexpected mechanism, combination possibilities for CDK 4/6 inhibitors

Researchers at Pfizer Inc., Weill Cornell Medical College and the Spanish National Cancer Research Center have shown that CDK 4/6 inhibitors could potentiate the effects of chemotherapy if they were given after chemotherapy. Ibrance (palbociclib, Pfizer Inc.), Verzenio (abemaciclib Eli Lilly and Co.) and Kisquali (ribociclib, Novartis AG) have moved the needle in metastatic breast cancer, and there is hope that as combination treatment, they will be able to do so in other tumor types as well. CDK 4/6 inhibitors prevent cell cycle entry, and so it has been assumed that combination treatment with chemotherapy, which acts on dividing cells, would not be beneficial to patients, an assumption that has been borne out in previous studies where the drugs were administered concurrently. The team showed, however, that administering CDK 4/6 inhibitors after chemotherapy in a mouse model of pancreatic cancer potentiated chemotherapy effects, apparently by affecting DNA repair and inducing a BRCA-like state. The authors concluded that their results point to “a new strategy to improve the current standard of care in a large number of patients.” They reported their findings in the Feb. 27, 2020, issue of Cancer Cell.

In SIV infection, gut integrity is retained, not repaired

Investigators at the University of Pittsburgh have shown that African green monkeys, the natural hosts of the HIV-related simian immunodeficiency virus (SIV), did not develop leaky guts or chronic inflammation at any time point after infection with SIV, which may underlie their ability to control the virus long term. Previous research had shown that African green monkeys retained intestinal integrity, but it was an open question whether the gut immune system did not mount an inflammatory immune response in the first place, or whether inflammatory damage was rapidly repaired. The team “observed only transient immune activation… during the acute infection and little to no increase in the markers of the aberrant chronic immune activation and inflammation typical of pathogenic HIV/SIV infections. We also confirmed that there are few alterations in the expression of genes linked to immune activation, inflammation or epithelial damage…Our study suggests early interventions aimed at repairing or preventing gut epithelial damage may represent a viable alternative to the current interventions intended to curb the deleterious consequences of HIV infection.” They published their study in the March 2, 2020, online issue of PLoS Pathogens.

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