Schizophrenia (SZ) is a devastating brain disease that affects about 1% of world population. Among the top genetic associations, zinc finger protein 804A (ZNF804A) gene encodes a zinc finger protein, associated with SZ and biolar disorder (BD). Copy number variants (CNVs) of ZNF804A have been observed in patients with autism spectrum disorders (ASDs), anxiety disorder, and BD, suggesting that ZNF804A is a dosage sensitive gene for brain development. However, its molecular functions have not been fully determined. Our previous interactomic study revealed that ZNF804A interacts with multiple proteins to control protein translation and neural development. ZNF804A is localized in the cytoplasm and neurites in the human cortex and is expressed in various types of neurons, including pyramidal, dopaminergic, GABAergic, and Purkinje neurons in mouse brain. To further examine the effect of gene dosage of ZNF804A on neurite morphology, both knockdown and overexpression of ZNF804A in primary neuronal cells significantly attenuate dendritic complex and spine formation. To determine the factors mediating these phenotypes, interestingly, three binding proteins of ZNF804A, galectin 1 (LGALS1), fasciculation and elongation protein zeta 1 (FEZ1) and ribosomal protein SA (RPSA), show different effects on reversing the deficits. LGALS1 and FEZ1 stimulate neurite outgrowth at basal level but RPSA shows no effect. Intriguingly, LGALS1 but not FEZ1, reverses the neurite outgrowth deficits induced by ZNF804A knockdown. However, FEZ1 and RPSA but not LGALS1, can ameliorate ZNF804A overexpression-mediated dendritic abnormalities. Thus, our results uncover a critical post-mitotic role of ZNF804A in neurite and synaptic development relevant to neurodevelopmental pathologies.
Background: Glioblastoma (GBM) is the most invasive brain tumors, and it is associated with high rates of recurrence and mortality. The purpose of this study was to investigate the expression of RBM8A in GBM and the potential influence of its expression on the disease.Methods: Levels of RBM8A mRNA in GBM patients and controls were examined in The Cancer Genome Atlas (TCGA), GSE16011 and GSE90604 databases. GBM samples in TCGA were divided into RBM8Ahigh and RBM8Alow groups. Differentially expressed genes (DEGs) between GBM patients and controls were identified, as were DEGs between RBM8Ahigh and RBM8Alow groups. DEGs common to both of these comparisons were analyzed for coexpression and regression analyses. In addition, we identified potential effects of RBM8A on competing endogenous RNAs, immune cell infiltration, methylation modifications, and somatic mutations.Results: RBM8A is expressed at significantly higher levels in GBM than control samples, and its level correlates with tumor purity. We identified a total of 488 mRNAs that differed between GBM and controls as well as between RBM8Ahigh and RBM8Alow groups, which enrichment analysis revealed to be associated mainly with neuroblast proliferation, and T cell immune responses. We identified 174 mRNAs that gave areas under the receiver operating characteristic curve >0.7 among coexpression module genes, of which 13 were significantly associated with overall survival of GBM patients. We integrated 11 candidate mRNAs through LASSO algorithm, then nomogram, risk score, and decision curve analyses were analyzed. We found that RBM8A may compete with DLEU1 for binding to miR-128-1-5p, and aberrant RBM8A expression was associations with tumor infiltration by immune cells. Some mRNAs associated with GBM prognosis also appear to be methylated or mutated.Conclusions: Our study strongly links RBM8A expression to GBM pathobiology and patient prognosis. The candidate mRNAs identified here may lead to therapeutic targets against the disease.
In Alzheimer's disease (AD), neuronal death is one of the key pathology. However, the initiation of neuronal death in AD is far from clear, and new targets are urgently needed to develop effective therapeutic methods. This study analyzed sequencing data from single-cell RNAseq and spatialomics, and revealed the impact of global single-cell mapping and cell spatial distribution relationships in early stage of AD. We found that microglia subpopulation Mic_PTPRG can anchor neurons based on ligand-receptor interaction pairs and cause ectopic expression of PTPRG in neurons during AD progression. PTPRG in neurons can bind and upregulate VIRMA expression, which in turn increases the level of m6A methylation, enhances PRKN transcript degradation and represses translation. Repressed PRKN expression blocks the clearance of damaged mitochondria in neurons, which in turn reprograms neuronal energy and nutrient metabolic pathways and leads to neuronal death during AD progression. This study elucidates novel mechanisms, by which the PTPRG-dependent microglia-synaptic modification may play a role in AD, providing a new scientific basis for potential therapeutic targets for AD.
Chemotherapy is one of the main treatments for hematologic malignancies.However, chemotherapy-induced peripheral neuropathy (CIPN) is one of the most common long-term toxic reactions in chemotherapy, and the occurrence of CIPN affects patients' quality of life and can cause interruption of chemotherapy in severe cases, thus reducing the efficacy of chemotherapy. We currently summarize the existing CIPN animal models, including the characteristics of several common animal models such as bortezomibinduced peripheral neuropathy, vincristine-induced peripheral neuropathy, and oxaliplatin-induced peripheral neuropathy. It was found that CIPN may lead to behavioral, histopathological, and neurophysiological changes inducing peripheral neuropathy. However, the mechanism of CIPN has not been fully elucidated, especially the prevention and treatment protocols need to be improved. Therefore, this review article summarizes the progress of research on CIPN animal models and the possible mechanisms and treatment of CIPN.
Scaffolding molecules are increasingly recognized as integral components of many signal transduction cascades. These are proteins without enzymatic function but contain membrane localization sequences, motifs for binding SH3 domains and tyrosine phosphorylation sites for binding SH2 domains. In hematopoietic cells, the Grb2-associated binder (Gab) family of scaffolding molecules couple to a plethora of cytokine receptors and receptor tyrosine kinases. There are three mammalian Gabs: Gab1, Gab2 and Gab3. Gab1 is ubiquitously expressed while the expression of Gab2 and Gab3 is more restricted. Each of the three Gabs has been knocked out: Gab1−/− mice are embryonically lethal, Gab2−/− mice are viable and show selective deficiencies in allergic responses and osteoclastogenesis while Gab3−/− mice are healthy. As most tissues and cell types contain multiple members, it is not clear if the limited phenotypes of the Gab2 and Gab3 knockout mice reflect redundant roles of the Gab proteins. We wish to elucidate what functions, if any, are played by the Gabs in Colony Stimulating Factor-1 (CSF-1)-dependent signaling and proliferation. CSF-1 is a critical growth, survival and differentiation factor for myelomonocytic cells. The IL-3-dependent myeloid progenitor cell line, 32D, is well characterized in our lab. Hematopoietic cells express predominantly Gab2 and Gab3. Real-time RTPCR data revealed that Gab2 and Gab3 are expressed at equivalent levels when copy numbers were determined. To evaluate the contribution of Gab2 and Gab3, we used an RNA interference approach. Multiple small hairpin (sh) RNAs targeted to different parts of the coding region or 3′UTR of Gab2 and Gab3 were screened by reporter assays (Mao and Lee, J. Cell Biol. 170:305) and the most effective shRNAs were chosen for further studies. To select for cells in which both Gab2 and Gab3 are silenced, shGab2 and shGab3 were cloned into a GFP- or dsRed-expressing lentiviral vector respectively. 32D cells were doubly infected with GFP and dsRed lentiviruses and doubly positive cells isolated by FACS sorting. Cell lines were established in which Gab2 and Gab3 were either silenced individually or in combination. Cells in which Gab2 alone was silenced showed a 50–60% reduction in proliferation after 4 d in the presence of maximal CSF-1 doses (10 nM) when compared to cells expressing an irrelevant shRNA, directed against a frog protein. In contrast, no difference was observed in response to maximal doses of IL-3 (10 ng/ml). CSF-1 provoked Akt, but not Erk activation, was significantly reduced in Gab2-silenced cells. When Gab3 was knocked down, the effect on CSF-1 or IL-3 mediated proliferation was not significant as was the effect on Akt and Erk activation. Surprisingly, when Gab2 and Gab3 were silenced together, we observed an increase of 30% in CSF-1-mediated proliferation after only 2 d in culture whereas proliferation in IL-3 was modestly reduced. Similar findings were observed in a clonal assay where clones were scored for size distribution. Inhibitor studies showed that doubly silenced cells were relatively insensitive to the PI3-kinase inhibitor, LY294002. This insensitivity was not observed with rapamycin, which inhibits mTOR. In summary, Gab2 appears to have a positive role in CSF-1 dependent proliferation, correlating with Akt activation while Gab3 appears to be largely dispensable for this function. However simultaneous suppression of Gab2 and Gab3 revealed that these proteins are also involved in modulating PI3-kinase-independent pathways that antagonize proliferation. Current studies are aimed at further characterizing this negative regulation.
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