Therapeutic targeting of the pathological triad of extrasynaptic NMDA receptor signaling in neurodegenerations
Bading reviews many neurodegenerative diseases sharing heightened extrasynaptic NMDA receptor signaling, which causes a pathological triad with mitochondrial dysfunction, deregulation of transcription, and loss of dendritic structures and connectivity. Areas of therapeutic objects are defined to guide the design of novel neuroprotective combination therapies.
Brief Definitive Report
Öhlund et al. develop a three-dimensional co-culture platform of neoplastic pancreatic ductal organoids and pancreatic stellate cells (PSCs) to characterize the dynamic crosstalk between cancer cells and stromal cells, and to address stromal heterogeneity. The co-cultures reveal the co-existence of two phenotypically distinct populations of PSCs, providing insights into PDA biology and prompting a reconsideration of interventional strategies.
Zhong et al. describe two novel roles for soluble TREM2 (sTREM2) in regulation of proinflammatory responses and prevention of cellular apoptosis in microglia.
Levine et al. investigate the extent to which regulatory T cells with either a monoclonal T cell receptor (TCR) or random TCR repertoire in place of their developmentally selected specificities maintain TCR-dependent gene expression and immunosuppressive function.
Volpi et al. demonstrate that hypomorphic EXTL3 mutations cause abnormalities of heparan sulfate composition, affect signaling in response to growth factors and cytokines, and perturb thymopoiesis, resulting in a novel genetic disease associating skeletal dysplasia, T cell immunodeficiency, and neurodevelopmental delay.
Laidlaw et al. show that Ephrin-B1 is a specific marker of mature germinal center (GC) B cells. Use of Ephrin-B1 allows for the identification of phenotypically distinct GC B cell subsets, including a population that may represent memory precursor B cells.
Using a novel human organ donor tissue resource, Gordon et al. reveal how CMV-specific T cells are distributed and function in multiple sites in the context of viral persistence, revealing new insights into immune control of CMV in the body.
Lyons et al. show that STAT3 negatively regulates TGF-β signaling via ERBIN and that cell-intrinsic deregulation of TGF-β pathway activation promotes the IL-4/IL-4Rα/GATA3 axis to support atopic phenotypes in humans.
One of the brain manifestations of tuberous sclerosis complex (TSC) is reduced myelination, but the underlying mechanism remains unclear. Ercan et al. demonstrate that mutant neurons overexpress a protein, connective tissue growth factor (CTGF), which impairs oligodendrocyte maturation and myelination.
Ismail et al. show that 27-hydroxycholesterol, a peripheral cholesterol metabolite capable of passing the blood–brain barrier, reduces brain glucose uptake by upregulating the renin-angiotensin system and inhibiting GLUT4. This alteration affects memory processes and is likely to have implications on neurodegenerative diseases.
Guitart et al. performed an in vivo genetic dissection of the Krebs cycle enzyme fumarate hydratase (Fh1) in the hematopoietic system. Their investigations revealed multifaceted functions of Fh1 in the regulation of hematopoietic stem cell biology and leukemic transformation.
Behrens et al. establish the interplay of activated FLT3 receptor and the phosphorylated RUNX1 transcription factor in uncoupling proliferation and differentiation signals in acute leukemia. These findings demonstrate that RUNX1 is a viable therapeutic target in FLT3-mutated AML.
Stanley et al. show that loss of Nol3 in mice leads to a myeloproliferative phenotype resembling primary myelofibrosis, with activation of JAK–STAT signaling and significant cellular and molecular resemblance to human disease. These findings provide a novel role for Nol3 in hematopoiesis and myeloid malignancies.
Analysis of mouse and human B lineage acute lymphoblastic leukemia identifies evolutionarily conserved targets of the tumor-suppressive transcription factor IKAROS, implicating CTNND1 in leukemia maintenance.
Schjerven et al. compare mouse and human models of pre–B ALL to define conserved target genes and pathways of the tumor suppressor Ikaros, revealing CTNND1 and the early hematopoietic cell-surface receptors SPN (CD43) and CD34 as novel Ikaros targets that each confer oncogenic growth advantage.
Rommel et al. reveal a novel RAG1/2-mediated insertion pathway, which has the potential to destabilize the lymphocyte genome and shares features with DNA insertions observed in human cancer.
Destabilizing the autoinhibitory conformation of Zap70 induces up-regulation of inhibitory receptors and T cell unresponsiveness
Hsu et al. show that a hypermorphic allele of Zap70, characterized by reduced autoinhibition, is associated with increased TCR signaling and triggers regulatory mechanisms by which negative selection and inhibitory receptors restrain TCR signaling to enforce T cell tolerance.
Boras et al. demonstrate that Skap2, via interaction with WASp, regulates actin polymerization and binding of talin-1 and kindlin-3 to the β2 integrin, thereby being indispensable for β2 integrin activation and neutrophil recruitment.