Journal of Neurochemistry最新文献

Retraction: G. Marwarha, T. Rhen, T. Schommer, and O. Ghribi, "The Oxysterol 27-Hydroxycholesterol Regulates α-Synuclein and Tyrosine Hydroxylase Expression Levels in Human Neuroblastoma Cells Through Modulation of Liver X Receptors and Estrogen Receptors-Relevance to Parkinson's Disease," Journal of Neurochemistry 119, no. 5 (2011): 1119-1136, https://doi.org/10.1111/j.1471-4159.2011.07497.x. The above article, published online on 23 September 2011 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal Editor-in-Chief, Andrew Lawrence; the International Society for Neurochemistry; and John Wiley & Sons Ltd. The retraction has been agreed upon following an investigation by the authors' institution, the University of North Dakota, which determined that Figure 2E was falsified by the corresponding author Othman Ghribi. Source data were not available for the article. The other authors were unaware of Ghribi's actions and not in any way involved. All authors were notified of the retraction decision, but did not respond.

Postural orthostatic tachycardia syndrome (POTS) is an adrenergic signaling disorder characterized by excessive plasma norepinephrine, postural tachycardia, and syncope. The norepinephrine transporter (NET) modulates adrenergic homeostasis via the reuptake of extracellular catecholamines and is implicated in the pathogenesis of adrenergic and neurological disorders. In this study, we reveal NET is palmitoylated in male Sprague-Dawley rats and Lilly Laboratory Cell Porcine Kidney (LLC-PK₁) cells. S-palmitoylation, or the addition of a 16-carbon saturated fatty acid, is a reversible post-translational modification responsible for the regulation of numerous biological mechanisms. We found that LLC-PK₁ NET is dynamically palmitoylated, and that inhibition with the palmitoyl acyltransferase (DHHC) inhibitor, 2-bromopalmitate (2BP) results in decreased NET palmitoylation within 90 min of treatment. This result was followed closely by a reduction in transport capacity, cell surface, and total cellular NET expression after 120 min of treatment. Increasing 2BP concentrations and treatment time revealed a nearly complete loss of total NET protein. Co-expression with individual DHHCs revealed a single DHHC enzyme, DHHC1, promoted wild-type (WT) hNET palmitoylation and elevated NET protein levels. The POTS-associated NET mutant, A457P, exhibits dramatically decreased transport capacity and cell surface levels which we have confirmed in the current study. In an attempt to recover A457P NET expression, we co-expressed the A457P variant with DHHC1 to drive expression as seen with the WT protein but instead saw an increase in NET N-terminal immuno-detectable forms and fragments. Elimination of a potential palmitoylation site at cysteine 44 in the N-terminal tail of hNET resulted in a low expression phenotype mimicking the A457P hNET variant. Further investigation of A457P NET palmitoylation and surface expression is necessary, but our preliminary novel findings reveal palmitoylation as a mechanism of NET regulation and suggest that dysregulation of this process may contribute to the pathogenesis of adrenergic disorders like POTS.

Interplanetary travel poses serious risks because of Galactic cosmic radiations (GCRs). A recent study by Sanghee et al. revealed long-term cognitive impairments in female mice exposed to a 33-beam GCR simulator, highlighting persistent risks for astronauts. The study's use of touchscreen tasks, similar to human cognitive tests, enhances its relevance for space missions. Additionally, the antioxidant/anti-inflammatory compound CDDO-EA showed potential in mitigating these cognitive deficits. While offering critical insights into GCR effects, the study emphasizes the need for further research into protective strategies, including dietary interventions, to ensure astronaut safety on extended missions beyond Earth's protective shield.

Infection and subsequent inflammatory processes negatively impact prognosis in individuals with traumatic brain injury (TBI). Tissue repair following TBI is tightly regulated by microglia, promoting or, importantly, preventing astrocyte-mediated repair processes, depending on the activation state of the neuroimmune cells. This study investigated the poorly understood mechanism linking proinflammatory microglia activation and astrocyte-mediated tissue repair using an in vitro mechanical injury model in mixed cortical cultures of rat neurons and glia. We hypothesized that proinflammatory activation disrupts the microglial response to colony-stimulating factor 1 (CSF-1), which stimulates microglia migration and proliferation, both essential for astrocyte-mediated tissue repair. Following mechanical damage, cultures were treated with lipopolysaccharide (LPS) and interferon-gamma (IFNγ) to induce a proinflammatory state. Immunocytochemical and biochemical analyses were used to evaluate glial repair. Proinflammatory activation dramatically impeded wound closure, reducing microglial levels via upregulation of the zinc-dependent disintegrin and metalloprotease 17 (ADAM17), leading to the cleavage of the CSF-1 receptor (CSF-1R). Indeed, pharmacological inhibition of ADAM17 effectively promoted wound closure during inflammation. Moreover, zinc chelation prevented ADAM17-mediated cleavage of CSF-1R and induced the release of trophic factors, dramatically improving tissue recovery. Our findings strongly identify ADAM17 as a primary regulator of CSF-1R-mediated signaling and establish a mechanism defining the association between pro-inflammatory microglial activation and tissue repair following injury.

Dopaminergic (DAnergic) dysfunction and imbalanced dopamine (DA) levels are known contributors to the pathogenesis of numerous psychiatric and neurodegenerative disorders. Of the many identified risk factors for DA-associated disorders, nuclear receptor subfamily 4 group A2 (NR4A2; or nuclear receptor related-1 protein (NURR1)), a transcription factor involved in DAnergic differentiation, has been associated with Parkinson's disease and attention deficit hyperactive disorder (ADHD). In zebrafish, transient loss of nr4a2 was previously shown to decrease tyrosine hydroxylase (TH) expression and impair locomotion. To further characterize the roles of the two zebrafish nr4a2 paralogs, nr4a2a, and nr4a2b, we produced targeted loss-of-function mutants and examined DAnergic neuron regeneration, oxidative respiration, and behavioral traits. The loss of nr4a2a function more closely recapitulated Parkinsonian phenotypes and affected neurotrophic factor gene expression. Conversely, nr4a2b mutants displayed behavioral symptoms reminiscent of mice deficient in Nr4a2 with increased neurotrophic output. In contrast, nr4a2b mutants also displayed increased metabolic input from non-mitochondrial sources indicative of high cytosolic reactive oxygen species and perturbed mitochondrial function. The nr4a2a mutants also showed increased maximal respiration, which may suggest a compensatory mechanism to meet the metabolic requirements of DAnergic neuron health. Overall, the zebrafish mutants generated in this study helped uncover molecular mechanisms involved in DA-related disease pathologies, and in the regeneration of DAnergic neurons.

Astrocytes are the principle glial cells of the central nervous system and play an active role in maintaining proper metabolism in surrounding neurons. Because of their involvement in metabolic control, it is likely that their physiology changes in response to metabolic diseases such as diabetes and associated diabetic retinopathy. Here, we investigated whether microstructural changes in astrocyte morphology occur during the early stages of chronic hyperglycemia that may be indicative of early pathogenic programs. We used MORF3 mice in conjunction with streptozotocin-induced hyperglycemia to investigate the morphology of single retinal astrocytes at an early timepoint in diabetic disease. We report that astrocytes initiate a morphological remodeling program, which depends on both the glycemic background and the presence of intravitreal injury, to alter the amount of the neuronal-associated pad and bristle microstructural motifs. Additionally, hyperglycemia increases astrocyte uptake of cholera toxin B, possibly reflecting changes in glycolipid and glycoprotein biosynthesis. Chronic hyperglycemia coupled with intravitreal injection of cholera toxin B also causes extensive leukocyte infiltration into the retina. Our results have important clinical relevance as current therapies for diabetic retinopathy involve intravitreal injection of pharmaceuticals in individuals with often poorly controlled blood glucose levels.

High-fat diet (HFD)-induced obesity induces peripheral inflammation and hypothalamic pathogenesis linking the activation of astrocytes and microglia. Clinical evidence indicates a positive correlation between obesity and psychiatric disorders, such as depression. The connectivity of the frontal-striatal (FS) circuit, involving the caudate putamen (CPu) and anterior cingulate cortex (ACC) within the prefrontal cortex (PFC), is known for its role in stress-induced depression. Thus, there is a need for a thorough investigation into whether chronic obesity-induced gliosis, characterized by the activation of astrocytes and microglia, in these brain regions of individuals with chronic obesity. The results revealed increased S100β⁺ astrocytes and Iba1⁺ microglia in the CPu and ACC of male obese mice, along with immune cell accumulation in meningeal lymphatic drainage. Activated GFAP⁺ astrocytes and Iba1⁺ microglia were observed in the corpus callosum of obese mice. Gliosis in the CPu and ACC was linked to elevated cleaved caspase-3 levels, indicating potential neural cell death by chronic HFD feeding. There was a loss of myelin and adenomatous polyposis coli (APC)⁺ oligodendrocytes (OLs) in the corpus callosum, an area known to be linked with injury to the CPu. Additionally, reduced levels of aquaporin-4 (AQP4), a protein associated within the glymphatic systems, were noted in the CPu and ACC, while ciliary neurotrophic factor (CNTF) gene expression was upregulated in these brain regions of obese mice. The in vitro study revealed that high-dose CNTF causing a trend of reduced astrocytic AQP4 expression, but it significantly impaired OL maturation. This pathological evidence highlights that prolonged HFD consumption induces persistent FS gliosis and demyelination in the corpus callosum. An elevated level of CNTF appears to act as a potential regulator, leading to AQP4 downregulation in the FS areas and demyelination in the corpus callosum. This cascade of events might contribute to neural cell damage within these regions and disrupt the glymphatic flow.

Oligodendrocytes, a type of glial cell in the central nervous system, have a critical role in the formation of myelin around axons, facilitating saltatory conduction, and maintaining the integrity of nerve axons. The dysregulation of oligodendrocyte differentiation and homeostasis have been implicated in a wide range of neurological diseases, including dysmyelinating disorders (e.g., Pelizaeus-Merzbacher disease), demyelinating diseases (e.g., multiple sclerosis), Alzheimer's disease, and psychiatric disorders. Therefore, unraveling the mechanisms of oligodendrocyte development, differentiation, and homeostasis is essential for understanding the pathogenesis of these diseases and the development of therapeutic interventions. Numerous studies have identified and analyzed the functions of transcription factors, RNA metabolic factors, translation control factors, and intracellular and extracellular signals involved in the series of processes from oligodendrocyte fate determination to terminal differentiation. DEAD-box proteins, multifunctional RNA helicases that regulate various intracellular processes, including transcription, RNA processing, and translation, are increasingly recognized for their diverse roles in various aspects of oligodendrocyte development, differentiation, and maintenance of homeostasis. This review introduces the latest insights into the regulatory networks of oligodendrocyte biology mediated by DEAD-box proteins.

The mechanisms underlying neuronal development and synaptic formation in the brain depend on intricate cellular and molecular processes. The neuronal membrane glycoprotein GPM6a promotes neurite elongation, filopodia/spine formation, and synapse development, yet its molecular mechanisms remain unknown. Since the extracellular domains of GPM6a (ECs) command its function, we investigated the interaction between ICAM5, the neuronal member of the intercellular adhesion molecule (ICAM) family, and GPM6a's ECs. Our study aimed to explore the functional relationship between GPM6a and ICAM5 in hippocampal culture neurons and cell lines. Immunostaining of 15 days in vitro (DIV) neurons revealed significant co-localization between endogenous GPM6a clusters and ICAM5 clusters in the dendritic shaft. These results were further corroborated by overexpressing GPM6a and ICAM5 in N2a cells and hippocampal neurons at 5 DIV. Moreover, results from the co-immunoprecipitations and cell aggregation assays prove the cis and trans interaction between both proteins in GPM6a/ICAM5 overexpressing HEK293 cells. Additionally, GPM6a and ICAM5 overexpression additively enhanced neurite length, the number of neurites in N2a cells, and filopodia formation in 5 DIV neurons, indicating their cooperative role. These findings highlight the dynamic association between GPM6a and ICAM5 during neuronal development, offering insights into their contributions to neurite outgrowth, filopodia formation, and cell-cell interactions.

The five-choice serial reaction time task (5CSRTT) is a test of attention that provides a well-validated ancillary measure of impulsive action, measured by premature responses. The task has been adapted for mice in touchscreen operant boxes, which is thought to offer improved test-retest reliability. Few studies have assessed the long-term stability of performance, including premature responding in this version of the task. We used the touchscreen 5CSRTT to conduct longitudinal testing of stability of premature responding following repeated behavioral and pharmacological manipulations. Male C57BL/6J mice were trained on a baseline version of the 5CSRTT. They were then tested on versions of the task in which the stimulus duration was reduced, and inter-trial intervals were elongated or varied within-session. Premature responding was subsequently tested following administration of pharmacological agents known to bi-directionally affect attention and impulsive action-cocaine, atomoxetine, and yohimbine. Mice were lastly re-tested 6 months later using the 5CSRTT with elongated inter-trial intervals. A reduced stimulus duration impacted attention, with reduced accuracy and increased omissions, but had no effect on premature responding. Both elongating and varying the inter-trial interval within-session increased premature responses. Mice showed similar and stable levels of increased premature responding 6 months later. Cocaine increased premature responding, though less than previously reported in rats. Atomoxetine reduced premature responding. Yohimbine had no effect on premature responding in the baseline task but decreased premature responding when tested using an elongated inter-trial interval. Overall, these results highlight that the touch screen adaptation of the 5CSRTT is an effective method for longitudinal testing of attention and impulsive action and remains sensitive to performance changes arising from repeated pharmacological and behavioral challenges.