Regulation Of Neuronal Survival Research Articles

Upregulation of mitochondrial PGK1 by ROS-TBC1D15 pathway promotes neuronal death after oxygen-glucose deprivation/reoxygenation injury

Phosphoglycerate kinase 1 (PGK1) is extensively located in the cytosol and mitochondria. The role of PGK1 in ischemic neuronal injury remains elusive. In the in vitro model of oxygen-glucose deprivation/reoxygenation (OGD/R), we showed that PGK1 expression was increased in cortical neurons. Knockdown of PGK1 led to a reduction of OGD/R-induced neuronal death. The expression of cytosolic PGK1 was reduced, but the levels of mitochondrial PGK1 were increased in OGD/R-insulted neurons. Inhibiting the activity of mitochondrial PGK1 alleviated the neuronal injury after OGD/R insult. We further showed that the protein levels of TBC domain family member 15 (TBC1D15) were decreased in OGD/R-insulted neurons. Knockdown of TBC1D15 led to increased levels of mitochondrial PGK1 after OGD/R insult in cortical neurons. Moreover, increased reactive oxygen species (ROS) resulted in a reduction of TBC1D15 in OGD/R-insulted neurons. These results suggest that the upregulation of mitochondrial PGK1 by ROS-TBC1D15 signaling pathway promotes neuronal death after OGD/R injury. Mitochondrial PGK1 may act as a regulator of neuronal survival and interventions in the PGK1-dependent pathway may be a potential therapeutic strategy.

The role of TrkB receptor signaling in Alzheimer’s disease

Alzheimer’s disease (AD) is one of the most prevalent neurodegenerative disorders among the elderly. However, there is no reliable drug for the treatment of AD, which is largely due to the unknown mechanisms and the lack of credible drug targets. Some studies demonstrated the hat the brain-derived neurotrophic factor/tropomyosin receptor kinase B (BDNF/TrkB) signaling pathway may be a potential therapeutic target for AD. As the most widely studied neurotrophin in the brain, BDNF has a high affinity for TrkB receptor and plays an important role in the regulation of neuronal survival, growth, and synaptic plasticity. Mechanistically, TrkB signaling cascade is considered to be the most important way in which BDNF exerts neuroprotective effects. The expression of TrkB receptor was also found to be significantly decreased in AD patients and AD animals compared with the control, suggesting the involvement of TrkB receptor and TrkB-dependent signal in AD pathogenesis. In this review, we aim to discuss the possible role of TrkB-dependent signal in AD pathogenesis, focusing on three major downstream pathways including phosphatidylinositol-3 kinase/protein kinase B (PI3K/AKT), extracellular regulated kinase (ERK), and phospholipase C-γ1 (PLC-γ1) pathways.

MANF regulates neuronal survival and UPR through its ER-located receptor IRE1α.

Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum (ER)-located protein with cytoprotective effects in neurons and pancreatic β cells invitro and in models of neurodegeneration and diabetes invivo. However, the exact mode of MANF action has remained elusive. Here, we show that MANF directly interacts with the ER transmembrane unfolded protein response (UPR) sensor IRE1α, and we identify the binding interface between MANF and IRE1α. The expression of wild-type MANF, but not its IRE1α binding-deficient mutant, attenuates UPR signaling by decreasing IRE1α oligomerization; phosphorylation; splicing of Xbp1, Atf6, and Txnip levels; and protecting neurons from ER stress-induced death. MANF-IRE1α interaction and not MANF-BiP interaction is crucial for MANF pro-survival activity in neurons invitro and is required to protect dopamine neurons in an animal model of Parkinson's disease. Our data show IRE1α as an intracellular receptor for MANF and regulator of neuronal survival.

Integrative analyses of maternal plasma cell-free DNA nucleosome footprint differences reveal chromosomal aneuploidy fetuses gene expression profile

BackgroundChromosomal aneuploidy is the most common birth defect. However, the developmental mechanism and gene expression profile of fetuses with chromosomal aneuploidy are relatively unknown, and the maternal immune changes induced by fetal aneuploidy remain unclear. The inability to obtain the placenta multiple times in real-time is a bottleneck in research on aneuploid pregnancies. Plasma cell-free DNA (cfDNA) carries the gene expression profile information of its source cells and may be used to evaluate the development of fetuses with aneuploidy and the immune changes induced in the mother owing to fetal aneuploidy.MethodsHere, we carried out whole-genome sequencing of the plasma cfDNA of 101 pregnant women carrying a fetus with trisomy (trisomy 21, n = 42; trisomy 18, n = 28; trisomy 13, n = 31) based on non-invasive prenatal testing (NIPT) screening and 140 normal pregnant women to identify differential genes according to the cfDNA nucleosome profile in the region around the transcription start sites (TSSs).ResultsThe plasma cfDNA promoter profiles were found to differ between aneuploid and euploid pregnancies. A total of 158 genes with significant differences were identified, of which 43 genes were upregulated and 98 genes were downregulated. Functional enrichment and signaling pathway analysis were performed based on Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases found that these signal pathways were mainly related to the coordination of developmental signals during embryonic development, the control of cell growth and development, regulation of neuronal survival, and immune regulation, such as the MAPK, Hippo, TGF-β, and Rap1 signaling pathways, which play important roles in the development of embryonic tissues and organs. Furthermore, based on the results of differential gene analysis, a total of 14 immune-related genes with significant differences from the ImmPort database were collected and analyzed. These significantly different immune genes were mainly associated with the maintenance of embryonic homeostasis and normal development.ConclusionsThese results suggest that the distribution characteristics of cfDNA nucleosomes in maternal plasma can be used to reflect the status of fetal development and changes of the immune responses in trisomic pregnancies. Overall, our findings may provide research ideas for non-invasive detection of the physiological and pathological states of other diseases.

The interplay between prior selection, mild intermittent exposure, and acute severe exposure in phenotypic and transcriptional response to hypoxia.

Hypoxia has profound and diverse effects on aerobic organisms, disrupting oxidative phosphorylation and activating several protective pathways. Predictions have been made that exposure to mild intermittent hypoxia may be protective against more severe exposure and may extend lifespan. Here we report the lifespan effects of chronic, mild, intermittent hypoxia, and short‐term survival in acute severe hypoxia in four clones of Daphnia magna originating from either permanent or intermittent habitats. We test the hypothesis that acclimation to chronic mild intermittent hypoxia can extend lifespan through activation of antioxidant and stress‐tolerance pathways and increase survival in acute severe hypoxia through activation of oxygen transport and storage proteins and adjustment to carbohydrate metabolism. Unexpectedly, we show that chronic hypoxia extended the lifespan in the two clones originating from intermittent habitats but had the opposite effect in the two clones from permanent habitats, which also showed lower tolerance to acute hypoxia. Exposure to chronic hypoxia did not protect against acute hypoxia; to the contrary, Daphnia from the chronic hypoxia treatment had lower acute hypoxia tolerance than normoxic controls. Few transcripts changed their abundance in response to the chronic hypoxia treatment in any of the clones. After 12 h of acute hypoxia treatment, the transcriptional response was more pronounced, with numerous protein‐coding genes with functionality in oxygen transport, mitochondrial and respiratory metabolism, and gluconeogenesis, showing upregulation. While clones from intermittent habitats showed somewhat stronger differential expression in response to acute hypoxia than those from permanent habitats, contrary to predictions, there were no significant hypoxia‐by‐habitat of origin or chronic‐by‐acute treatment interactions. GO enrichment analysis revealed a possible hypoxia tolerance role by accelerating the molting cycle and regulating neuron survival through upregulation of cuticular proteins and neurotrophins, respectively.

Off the Clock: the Non-canonical Roles of Cyclin-Dependent Kinases in Neural and Glioma Stem Cell Self-Renewal.

Glioma stem cells (GSCs) are thought to drive growth and therapy resistance in glioblastoma (GBM) by "hijacking" at least a subset of signaling pathways active in normal neural stem cells (NSCs). Though the origins of GSCs still remain elusive, uncovering the mechanisms of self-renewing division and cell differentiation in normal NSCs has shed light on their dysfunction in GSCs. However, the distinction between self-renewing division pathways utilized by NSC and GSC becomes critical when considering options for therapeutically targeting signaling pathways that are specifically active or altered in GSCs. It is well-established that cyclin-dependent kinases (CDKs) regulate the cell cycle, yet more recent studies have shown that CDKs also play important roles in the regulation of neuronal survival, metabolism, differentiation, and self-renewal. The intimate relationship between cell cycle regulation and the cellular programs that determine self-renewing division versus cell differentiation is only beginning to be understood, yet seems to suggest potential differential vulnerabilities in GSCs. In this timely review, we focus on the role of CDKs in regulating the self-renewal properties of normal NSCs and GSCs, highlighting novel opportunities to therapeutically target self-renewing signaling pathways specifically in GBM.

Exploring the role of interleukin-27 as a regulator of neuronal survival in central nervous system diseases.

Interleukin-27 is a pleiotropic cytokine that is involved in tissue responses to infection, cell stress, neuronal disease, and tumors. Recent studies in various tissues indicate that interleukin-27 has complex activating and inhibitory properties in innate and acquired immunity. The availability of recombinant interleukin-27 protein and mice with genetic deletions of interleukin-27, its receptors and signaling mediators have helped define the role of interleukin-27 in neurodegenerative diseases. Interleukin-27 has been well-characterized as an important regulator of T cell activation and differentiation that enhances or suppresses T cell responses in autoimmune conditions in the central nervous system. Evidence is also accumulating that interleukin-27 has neuroprotective activities in the retina and brain. Interleukin-27 is secreted from and binds to infiltrating microglia, macrophage, astrocytes, and even neurons and it promotes neuronal survival by regulating pro- and anti-inflammatory cytokines, neuroinflammatory pathways, oxidative stress, apoptosis, autophagy, and epigenetic modifications. However, interleukin-27 can have the opposite effect and induce inflammation and cell death in certain situations. In this review, we describe the current understanding of regulatory activities of interleukin-27 on cell survival and inflammation and discuss its mechanisms of action in the brain, spinal cord, and retina. We also review evidence for and against the therapeutic potential of interleukin-27 for dampening harmful neuroinflammatory responses in central nervous system diseases.

The ESTROGEN-MECHANISM OF NEUROPROTECTION

Estrogen is an important steroid hormone signal that regulates multiple tissues and functions in the body.The brain is an important target organ for estrogen. In addition to direct effects, estrogen influences brain function through effects on the vasculature and the immune system. Estrogen influences several neurotransmitter systems, including acetylcholine, serotonin, noradrenalin, and glutamate. There are complex mechanisms that underlie estrogen neuroprotective and neurotrophic actions (genomic, non-genomic kinase signalic pathways and membrane estrogen receptors pathways). Estradiol induces gene transcription and rapid membrane signaling mediated by estrogen receptor alpha (ERα), estrogen receptor-beta (ERβ), and a recently characterized G-protein coupled estrogen receptor, each with distinct distributions and ability to influence estradiol-dependent signaling.Vector-mediated expression of estrogen receptors in the hippocampus provides an innovative research approach and suggests that memory depends on the relative expression of ERα and ERβ interacting with estradiol levels.The potential role of estrogen as a neuroprotective factor and a multicellular mode of estrogen action in the regulation of neuronal survival and neurotrophism is discussed, as are potential future directions for the field. Key words: estrogen; estrogen  receptors; steroid hormone;  neuroprotection

ZFP36 protects against oxygen-glucose deprivation/reoxygenation-induced mitochondrial fragmentation and neuronal apoptosis through inhibiting NOX4-DRP1 pathway

The imbalance of mitochondrial dynamics plays an important role in the pathogenesis of cerebral ischemia/reperfusion (I/R) injury. Zinc-finger protein 36 (ZFP36) has been documented to have neuroprotective effects, however, whether ZFP36 is involved in the regulation of neuronal survival during cerebral I/R injury remains unknown. In this study, we found that the transcriptional and translational levels of ZFP36 were increased in immortalized hippocampal HT22 neuronal cells after oxygen-glucose deprivation/reoxygenation (OGD/R) treatment. ZFP36 gene silencing exacerbated OGD/R-induced dynamin-related protein 1 (DRP1) activity, mitochondrial fragmentation, oxidative stress and neuronal apoptosis, whereas ZFP36 overexpression exhibited the opposite effects. Besides, we found that NADPH oxidase 4 (NOX4) was upregulated by OGD/R, and NOX4 inhibition remarkably attenuated OGD/R-instigated DRP1 activity, mitochondrial fragmentation and neuronal apoptosis. Further study demonstrated that ZFP36 targeted NOX4 mRNA directly by binding to the AU-rich elements (AREs) in the NOX4 3′-untranslated regions (3′-UTR) and inhibited NOX4 expression. Taken together, our data indicate that ZFP36 protects against OGD/R-induced neuronal injury by inhibiting NOX4-mediated DRP1 activation and excessive mitochondrial fission. Pharmacological targeting of ZFP36 to suppress excessive mitochondrial fission may provide new therapeutic strategies in the treatment of cerebral I/R injury.

Coming Back to Physiology: Extra Hepatic Functions of Proprotein Convertase Subtilisin/Kexin Type 9.

Neuronal apoptosis regulated convertase-1 (NARC-1), now mostly known as proprotein convertase subtilisin/kexin type 9 (PCSK9), has received a lot of attention due to the fact that it is a key regulator of the low-density lipoprotein (LDL) receptor (LDL-R) and is therefore involved in hepatic LDL clearance. Within a few years, therapies targeting PCSK9 have reached clinical practice and they offer an additional tool to reduce blood cholesterol concentrations. However, PCSK9 is almost ubiquitously expressed in the body but has less well-understood functions and target proteins in extra hepatic tissues. As such, PCSK9 is involved in the regulation of neuronal survival and protein degradation, it affects the expression of the epithelial sodium channel (ENaC) in the kidney, it interacts with white blood cells and with cells of the vascular wall, and it modifies contractile activity of cardiomyocytes, and contributes to the regulation of cholesterol uptake in the intestine. Moreover, under stress conditions, signals from the kidney and heart can affect hepatic expression and thereby the plasma concentration of PCSK9 which then in turn can affect other target organs. Therefore, there is an intense relationship between the local (autocrine) and systemic (endocrine) effects of PCSK9. Although, PCSK9 has been recognized as a ubiquitously expressed modifier of cellular function and signaling molecules, its physiological role in different organs is not well-understood. The current review summarizes these findings.

Protein expression of MEF2C during the critical period for visual development in vervet monkeys

During the early development of the visual cortex, there is a critical period when neuronal connections are highly sensitive to changes in visual input. Deprivation of visual stimuli during the critical period elicits robust anatomical and physiological rearrangements in the monkey visual cortex and serves as an excellent model for activity-dependent neuroplasticity. DNA microarray experiments were previously performed in our lab to analyze gene expression patterns in area V1 of vervet monkeys subjected to monocular deprivation (MD). An interesting candidate identified in its screen was myocyte enhancer-binding factor 2C (MEF2C), a transcription factor linked to neuronal survival. Consistent with the microarray data, we show that there is a qualitative increase in MEF2C protein expression in area V1 of infant as compared to adult vervet monkeys. Our results suggest that the regulation of neuronal survival is one of the molecular mechanisms underlying the critical period for visual cortical neuroplasticity.

YTHDC1 mitigates ischemic stroke by promoting Akt phosphorylation through destabilizing PTEN mRNA

YTH Domain Containing 1 (YTHDC1) is one of the m6A readers that is essential for oocyte development and tumor progression. The role of YTHDC1 in neuronal survival and ischemic stroke is unknown. Here, we found that YTHDC1 was unregulated in the early phase of ischemic stroke. Knockdown of YTHDC1 exacerbated ischemic brain injury and overexpression of YTHDC1 protected rats against brain injury. Mechanistically, YTHDC1 promoted PTEN mRNA degradation to increase Akt phosphorylation, thus facilitating neuronal survival in particular after ischemia. These data identify YTHDC1 as a novel regulator of neuronal survival and modulating m6A reader YTHDC1 may provide a potential therapeutic target for ischemic stroke.

BDNF and nicotine dependence: associations and potential mechanisms.

Smoking is the leading preventable cause of death worldwide and tobacco addiction has become a serious public health problem. Nicotine is the main addictive component of tobacco, and the majority of people that smoke regularly develop nicotine dependence. Nicotine addiction is deemed to be a chronic mental disorder. Although it is well known that nicotine binds to the nicotinic acetylcholine receptors (nAChRs) and activates the mesolimbic dopaminergic system (MDS) to generate the pleasant and rewarding effects, the molecular mechanisms of nicotine addiction are not fully understood. Brain-derived neurotrophic factor (BDNF) is the most prevalent growth factor in the brain, which regulates neuron survival, differentiation, and synaptic plasticity, mainly through binding to the high affinity receptor tyrosine kinase receptor B (TrkB). BDNF gene polymorphisms are associated with nicotine dependence and blood BDNF levels are altered in smokers. In this review, we discussed the effects of nicotine on BDNF expression in the brain and summarized the underlying signaling pathways, which further indicated BDNF as a key regulator in nicotine dependence. Further studies that aim to understand theneurobiological mechanism of BDNF in nicotine addcition would provide a valuable reference for quitting smoking and developing the treatment of other addictive substances.

Downregulation of Adhesion Molecule CHL1 in B Cells but Not T Cells of Patients with Major Depression and in the Brain of Mice with Chronic Stress.

Depression is a common serious mental disorder with unclear pathogenesis. Currently, specific diagnostic biomarkers are yet to be characterized. The close homolog of L1 (CHL1) is a L1 family cell adhesion molecule involved in the regulation of neuronal survival and growth. Although genome-wide expression profiling of human lymphoblastoid cell lines (LCLs) reported neural cell adhesion molecule (NCAM) L1 as a tentative biomarker for selective serotonin reuptake inhibitor (SSRI) antidepressant response, the involvement of CHL1 in depression is unclear. In this study, using a well-established chronic unpredictable mild stress (CUMS) depression mouse model, we examined the mRNA and protein expression of CHL1 in normal control, CUMS, vehicle (VEH), fluoxetine (FLU), and clozapine (CLO) groups. We found that in the CUMS group, both mRNA and protein expression of CHL1 were downregulated in both the hippocampus and the cortex. Treatment of CUMS mice with FLU and CLO reversed CHL1 mRNA and protein expression. In the human study, we showed that CHL1 expression was significantly downregulated in monocytes of unipolar and bipolar depressive patients compared with healthy donors (HD) at both mRNA and protein levels. Consistently, ELISA showed that CHL1 levels in the serum of patients with depression were reduced and negatively correlated with their HRSD-21 scores. Further flow cytometry studies showed that the reduced number of CHL1 positive CD19+ and CD20+ B cells of patients with depression was subsequently reversed with antidepressant treatment. Our findings suggested that downregulation of CHL1 from both immune cells and the brain may be linked to the immunopathogenesis of depression. In conclusion, CHL1 may be an important predictive marker for both diagnosis and treatment outcome of depression.

Knockdown of TRIM22 Relieves Oxygen-Glucose Deprivation/Reoxygenation-Induced Apoptosis and Inflammation Through Inhibition of NF-κB/NLRP3 Axis.

Tripartite motif-containing 22 (TRIM22) has been documented to participate in numerous cellular activities during human diseases. However, whether TRIM22 is involved in the regulation of neuronal survival during the progression of cerebral ischemia/reperfusion (I/R) injury remains unknown. In the present study, treatment of HCN-2 cells with oxygen-glucose deprivation/reoxygenation (OGD/R) markedly upregulated TRIM22 expression. A significant increase in TRIM22 expression was observed in the ischemic cortex tissues from middle cerebral artery occlusion/reperfusion mice. OGD/R inhibited the viability and induced the apoptosis of HCN-2 cells, which was accompanied by an increase in caspase-3 activity and an increase in LDH release. Furthermore, OGD/R increased the levels of tumor necrosis factor-alpha, interleukin (IL)-1 beta, IL-6, and monocyte chemoattractant protein-1 and induced NLRP3 inflammasome activation, as evidenced by increases in NACHT, LRR and PYD domains-containing protein 3, apoptosis-associated speck-like protein containing a caspase recruitment domain and cleaved caspase-1 expression and caspase-1 activity. However, these changes induced by OGD/R were blocked by silencing of TRIM22. In addition, TRIM22 regulated NF-κB activity in HCN-2 cells undergoing OGD/R stimulation. Furthermore, inhibition of NF-κB by pyrrolidine dithiocarbamate inhibited OGD/R-induced NLRP3 inflammasome activation in HCN-2 cells. Taken together, silencing of TRIM22 protects neurons against OGD/R-induced apoptosis and inflammation. The anti-inflammatory effect of TRIM22 knockdown was the consequence of inhibition of NF-κB/NLRP3 axis. TRIM22 may be a potential target for treating cerebral I/R injury.

The Effects of Leptin on Glial Cells in Neurological Diseases.

It is known that various endocrine modulators, including leptin and ghrelin, have neuroprotective roles in neurological diseases. Leptin is a hormone produced by adipocytes and was originally identified as a gene related to obesity in mice. The leptin receptors in the hypothalamus are the main target for the homeostatic regulation of body weight. Recent studies have demonstrated that leptin receptors are also expressed in other regions of the central nervous system (CNS), such as the hippocampus, cerebral cortex, and spinal cord. Accordingly, these studies identified the involvement of leptin in the regulation of neuronal survival and neural development. Furthermore, leptin has been shown to have neuroprotective functions in animal models of neurological diseases and demyelination. These observations also suggest that dysregulation of leptin signaling may be involved in the association between neurodegeneration and obesity. In this review, we summarize novel functions of leptin in animal models of neurodegenerative diseases. Specifically, we focus on the emerging evidence for the role of leptin in non-neuronal cells in the CNS, including astrocytes, microglia, and oligodendrocytes. Understanding leptin-mediated neuroprotective signals and molecular mechanisms underlying remyelination will be helpful to establish therapeutic strategies against neurological diseases.

MicroRNA‑217 inhibition relieves cerebral ischemia/reperfusion injury by targeting SIRT1.

MicroRNAs (miRs) have been proposed to be involved in the pathological processes of cerebral ischemia/reperfusion (CIR) injury. The present study aimed to investigate the potential role and molecular mechanisms of miR-217 in the regulation of neuronal survival in CIR injury. To perform the investigation, an in vitro cellular model of CIR injury was established by treating neurons with oxygen-glucose deprivation and reoxygenation (OGD/R). miR-217 levels in neurons were detected using reverse transcription-quantitative PCR. The association between miR-217 and sirtuin 1 (SIRT1) was identified using TargetScan and validated in a dual-luciferase reporter assay. Cell viability and apoptosis were measured using a Cell Counting Kit-8 assay and flow cytometry, respectively. The release of lactate dehydrogenase, and the production of proinflammatory factors and oxidative stress biomarkers were analyzed by ELISAs and using specific assay kits. It was revealed that miR-217 was significantly upregulated in OGD/R-treated neurons. SIRT1 was a direct target of miR-217, and was downregulated in neurons following OGD/R treatment. Downregulation of miR-217 significantly ameliorated OGD/R-induced neuronal injury, inflammatory responses and oxidative stress. The effects of miR-217 inhibitor on OGD/R treated neurons were attenuated by SIRT1 knockdown. Additionally, western blotting revealed that the SIRT1/AMP-activated protein kinase-α/NF-κB pathway was partially involved in the regulation of OGD/R-induced neuronal injury by miR-217. In conclusion, the data of the present study indicated that the downregulation of miR-217 protected neurons against OGD/R-induced injury by targeting SIRT1.

Regulation of Neuronal Survival and Axon Growth by a Perinuclear cAMP Compartment.

cAMP signaling is known to be critical in neuronal survival and axon growth. Increasingly the subcellular compartmentation of cAMP signaling has been appreciated, but outside of dendritic synaptic regulation, few cAMP compartments have been defined in terms of molecular composition or function in neurons. Specificity in cAMP signaling is conferred in large part by A-kinase anchoring proteins (AKAPs) that localize protein kinase A and other signaling enzymes to discrete intracellular compartments. We now reveal that cAMP signaling within a perinuclear neuronal compartment organized by the large multivalent scaffold protein mAKAPα promotes neuronal survival and axon growth. mAKAPα signalosome function is explored using new molecular tools designed to specifically alter local cAMP levels as studied by live-cell FRET imaging. In addition, enhancement of mAKAPα-associated cAMP signaling by isoform-specific displacement of bound phosphodiesterase is demonstrated to increase retinal ganglion cell survival in vivo in mice of both sexes following optic nerve crush injury. These findings define a novel neuronal compartment that confers cAMP regulation of neuroprotection and axon growth and that may be therapeutically targeted in disease.SIGNIFICANCE STATEMENT cAMP is a second messenger responsible for the regulation of diverse cellular processes including neuronal neurite extension and survival following injury. Signal transduction by cAMP is highly compartmentalized in large part because of the formation of discrete, localized multimolecular signaling complexes by A-kinase anchoring proteins. Although the concept of cAMP compartmentation is well established, the function and identity of these compartments remain poorly understood in neurons. In this study, we provide evidence for a neuronal perinuclear cAMP compartment organized by the scaffold protein mAKAPα that is necessary and sufficient for the induction of neurite outgrowth in vitro and for the survival of retinal ganglion cells in vivo following optic nerve injury.

MiR-153 regulates cardiomyocyte apoptosis by targeting Nrf2/HO-1 signaling.

MicroRNAs (miRNAs) play various roles in the regulation of human disease, including cardiovascular diseases. MiR-153 has been previously shown to be involved in regulating neuron survival during cerebral ischemia/reperfusion (I/R) injury. However, whether miR-153 is involved in I/R-induced cardiomyocyte apoptosis remains to be elucidated. In this study, we aimed to explore the role of miR-153 in the regulation of I/R-induced cardiomyocyte apoptosis and to investigate the miR-153-mediated molecular signaling pathway responsible for its effect on cardiomyocytes using an oxygen-glucose deprivation and reoxygenation (OGD/R) cellular model. We found that OGD/R treatment induced significant upregulation of miR-153 in cardiomyocytes causing reactive oxygen species (ROS) production and cell apoptosis signaling activation and subsequently leading to cardiomyocyte apoptosis. Suppression of miR-153 protected cardiomyocytes against OGD/R treatment. We further identified that nuclear factor-like 2 (Nrf2) is a functional target of miR-153. Nrf2/ heme oxygenase-1 (HO-1) signaling plays a critical role in miR-153 regulated OGD/R-induced cardiomyocyte apoptosis. Our study indicates that the inhibition of miR-153 or restoration of Nrf2 may serve as a potential therapeutic strategy for ischemia/reperfusion injury prevention.

Neurotrophin Responsiveness of Sympathetic Neurons Is Regulated by Rapid Mobilization of the p75 Receptor to the Cell Surface through TrkA Activation of Arf6.

The p75 neurotrophin receptor (p75NTR) plays an integral role in patterning the sympathetic nervous system during development. Initially, p75NTR is expressed at low levels as sympathetic axons project toward their targets, which enables neurotrophin-3 (NT3) to activate TrkA receptors and promote growth. Upon reaching nerve growth factor (NGF) producing tissues, p75NTR is upregulated, resulting in formation of TrkA-p75 complexes, which are high-affinity binding sites selective for NGF, thereby blunting NT3 signaling. The level of p75NTR expressed on the neuron surface is instrumental in regulating trophic factor response; however, the mechanisms by which p75NTR expression is regulated are poorly understood. Here, we demonstrate a rapid, translation independent increase in surface expression of p75NTR in response to NGF in rat sympathetic neurons. p75NTR was mobilized to the neuron surface from GGA3-postitive vesicles through activation of the GTPase Arf6, which was stimulated by NGF, but not NT3 binding to TrkA. Arf6 activation required PI3 kinase activity and was prevented by an inhibitor of the cytohesin family of Arf6 guanine nucleotide exchange factors. Overexpression of a constitutively active Arf6 mutant (Q67L) was sufficient to significantly increase surface expression of p75NTR even in the absence of NGF. Functionally, expression of active Arf6 markedly attenuated the ability of NT3 to promote neuronal survival and neurite outgrowth, whereas the NGF response was unaltered. These data suggest that NGF activation of Arf6 through TrkA is critical for the increase in p75NTR surface expression that enables the switch in neurotrophin responsiveness during development in the sympathetic nervous system.SIGNIFICANCE STATEMENT p75NTR is instrumental in the regulation of neuronal survival and apoptosis during development and is also implicated as a contributor to aberrant neurodegeneration in numerous conditions. Therefore, a better understanding of the mechanisms that mediate p75NTR surface availability may provide insight into how and why neurodegenerative processes manifest and reveal new therapeutic targets. Results from this study indicate a novel mechanism by which p75NTR can be rapidly shuttled to the cell surface from existing intracellular pools and explores a unique pathway by which NGF regulates the sympathetic innervation of target tissues, which has profound consequences for the function of these organs.