Exploiting the gut microbiome for brain tumour treatment.

Increasing evidence suggests that the gut microbiome plays a key role in a host of pathological conditions, including cancer. Indeed, the bidirectional communication that occurs between the gut and the brain, known as the 'gut-brain axis,' has recently been implicated in brain tumour pathology. Here, we focus on current research that supports a gut microbiome-brain tumour link with emphasis on high-grade gliomas, the most aggressive of all brain tumours, and the impact on the glioma tumour microenvironment.

Bi-allelic NRXN1α deletion in microglia derived from iPSC of an autistic patient increases interleukin-6 production and impairs supporting function on neuronal networking.

Autism spectrum disorder (ASD) is a set of heterogeneous neurodevelopmental conditions, with a highly diverse genetic hereditary component, including altered neuronal circuits, that has an impact on communication skills and behaviours of the affected individuals. Beside the recognised role of neuronal alterations, perturbations of microglia and the associated neuroinflammatory processes have emerged as credible contributors to aetiology and physiopathology of ASD. Mutations in NRXN1, a member of the neurexin family of cell-surface receptors that bind neuroligin, have been associated to ASD.

Assessing mRNA translation in mouse adult microglia and bone-marrow-derived macrophages.

Protein synthesis, or mRNA translation, is the biological process through which genetic information stored in messenger RNAs is encoded into proteins. Here, we present an optimized protocol for assessing the translation rate in mouse adult microglia and cultured bone-marrow-derived macrophages. We describe steps for isolating cells, treating them with a puromycin-analog probe, and fluorescently labeling the puromycylated-polypeptide chains.

ARG1-expressing microglia show a distinct molecular signature and modulate postnatal development and function of the mouse brain.

Molecular diversity of microglia, the resident immune cells in the CNS, is reported. Whether microglial subsets characterized by the expression of specific proteins constitute subtypes with distinct functions has not been fully elucidated. Here we describe a microglial subtype expressing the enzyme arginase-1 (ARG1; that is, ARG1 microglia) that is found predominantly in the basal forebrain and ventral striatum during early postnatal mouse development.

Proteome integral solubility alteration high-throughput proteomics assay identifies Collectin-12 as a non-apoptotic microglial caspase-3 substrate.

Caspases are a family of proteins mostly known for their role in the activation of the apoptotic pathway leading to cell death. In the last decade, caspases have been found to fulfill other tasks regulating the cell phenotype independently to cell death. Microglia are the immune cells of the brain responsible for the maintenance of physiological brain functions but can also be involved in disease progression when overactivated.

SETD2 transcriptional control of ATG14L/S isoforms regulates autophagosome-lysosome fusion.

Macroautophagy/autophagy is an evolutionarily conserved and tightly regulated catabolic process involved in the maintenance of cellular homeostasis whose dysregulation is implicated in several pathological processes. Autophagy begins with the formation of phagophores that engulf cytoplasmic cargo and mature into double-membrane autophagosomes; the latter fuse with lysosomes/vacuoles for cargo degradation and recycling. Here, we report that yeast Set2, a histone lysine methyltransferase, and its mammalian homolog, SETD2, both act as positive transcriptional regulators of autophagy.

ULK3-dependent activation of GLI1 promotes DNMT3A expression upon autophagy induction.

Macroautophagy/autophagy is a tightly regulated catabolic process, which contributes at baseline level to cellular homeostasis, and upon its stimulation to the adaptive cellular response to intra- and extracellular stress stimuli. Decrease of autophagy activity is occurring upon aging and thought to contribute to age-related-diseases. Recently, we uncovered, upon autophagy induction, the role of DNMT3A (DNA methyltransferase 3 alpha)-mediated DNA methylation on expression of the MAP1LC3 (microtubule associated protein 1 light chain 3) proteins, core components of the autophagy pathway, which resulted in reduced baseline autophagy activity.

Inhibition of microglial EZH2 leads to anti-tumoral effects in pediatric diffuse midline gliomas.

Background: Diffuse intrinsic pontine gliomas (DIPG), within diffuse midline gliomas are aggressive pediatric brain tumors characterized by histone H3-K27M mutation. Small-molecule inhibitors for the EZH2-H3K27 histone methyltransferase have shown promise in preclinical animal models of DIPG, despite having little effect on DIPG cells . Therefore, we hypothesized that the effect of EZH2 inhibition could be mediated through targeting of this histone modifying enzyme in tumor-associated microglia.

Atg7 deficiency in microglia drives an altered transcriptomic profile associated with an impaired neuroinflammatory response.

Microglia, resident immunocompetent cells of the central nervous system, can display a range of reaction states and thereby exhibit distinct biological functions across development, adulthood and under disease conditions. Distinct gene expression profiles are reported to define each of these microglial reaction states. Hence, the identification of modulators of selective microglial transcriptomic signature, which have the potential to regulate unique microglial function has gained interest.

Multifaceted microglia - key players in primary brain tumour heterogeneity.

Microglia are the resident innate immune cells of the immune-privileged CNS and, as such, represent the first line of defence against tissue injury and infection. Given their location, microglia are undoubtedly the first immune cells to encounter a developing primary brain tumour. Our knowledge of these cells is therefore important to consider in the context of such neoplasms.

The DNA methyltransferase DNMT3A contributes to autophagy long-term memory.

Macroautophagy/autophagy is a conserved catabolic pathway that targets cytoplasmic components for their degradation and recycling in an autophagosome-dependent lysosomal manner. Under physiological conditions, this process maintains cellular homeostasis. However, autophagy can be stimulated upon different forms of cellular stress, ranging from nutrient starvation to exposure to drugs.

Microglial phagocytosis in aging and Alzheimer's disease.

Microglia are the innate immune cells of the brain, which maintain homeostasis by constantly scanning and surveying the environment with their highly ramified processes. In order to exert this function, they need to phagocytose synapses as well as debris and dead cells, a process that is further amplified in pathological conditions. Importantly, it has been shown that microglia phagocytic capacity is altered in the course of neurodegenerative disease, for which aging is one of the highest risk factors.