SorLA restricts TNFα release from microglia to shape a glioma-supportive brain microenvironment.

SorLA, encoded by the gene SORL1, is an intracellular sorting receptor of the VPS10P domain receptor gene family. Although SorLA is best recognized for its ability to shuttle target proteins between intracellular compartments in neurons, recent data suggest that also its microglial expression can be of high relevance for the pathogenesis of brain diseases, including glioblastoma (GBM). Here, we interrogated the impact of SorLA on the functional properties of glioma-associated microglia and macrophages (GAMs). In the GBM microenvironment, GAMs are re-programmed and lose the ability to elicit anti-tumor responses. Instead, they acquire a glioma-supporting phenotype, which is a key mechanism promoting glioma progression. Our re-analysis of published scRNA-seq data from GBM patients revealed that functional phenotypes of GAMs are linked to the level of SORL1 expression, which was further confirmed using in vitro models. Moreover, we demonstrate that SorLA restrains secretion of TNFα from microglia to restrict the inflammatory potential of these cells. Finally, we show that loss of SorLA exacerbates the pro-inflammatory response of microglia in the murine model of glioma and suppresses tumor growth.

Syngeneic Mouse Model of Glioblastoma: Intracranial Implantation of GL261 Cells.

Glioblastoma (GBM) is the most aggressive and prevalent primary brain malignancy in adults. Current treatments provide limited benefit, and thus, the median overall survival of GBM patients is only 15 months. GBM progression is highly dependent on its ability to evade immune response, so understanding the mechanisms behind GBM-driven immunosuppression seems crucial for designing more efficient therapies. Animal models of GBM constitute a convenient tool in glioma research, and several different approaches have been already developed to model this disease in vivo, including genetic and xenograft models. Here, we describe a murine syngeneic model of glioma which recapitulates many of the key features of human disease, including complex tumor microenvironment. We present an optimized protocol for stereotactic intracranial implantation of GL261 cells into C57BL/6 mice which results in tumor growth in the striatum. This model has been widely used to get insight into glioma biology, as well as in the studies aiming at the development and validation of new therapeutic approaches.

Everything on the right place ­ the role of VPS10P receptors in intracellular protein sorting / Wszystko na swoim miejscu ­ rola receptorów VPS10P w komórkowej segregacji bialek.

VPS10P (vacuolar protein sorting 10 protein) domain receptors consitute a family of sorting receptors which are responsible for directing their protein cargo into destined subcellular localization. Functions of VPS10P domain receptors have been well-described in neurons, where efficient sorting of proteins is crucial for cell viability. Dysfunctions in neuronal actions of VPS10P domain receptors are linked to disturbances in neuronal plasticity and development of neurodegenerative disorders. VPS10P domain receptors are also crucial for lipid metabolism, mainly through transport of lipolytic enzymes or influencing the uptake of lipoproteins by the cells. Emerging evidence suggests that VPS10P domain receptors can play important roles in immune response evoked by immune or glial cells. They are also key players in pathogenesis of cancers.