Mahmoud Ali Eladawi

The amygdala, crucial for mood, anxiety, fear, and reward regulation, shows neuroanatomical and molecular divergence in psychiatric disorders like schizophrenia, bipolar disorder and major depression. This region is also emerging as an important regulator of metabolic and immune pathways. The goal of this study is to address the paucity of molecular studies in the human amygdala. We hypothesize that diagnosis-specific gene expression alterations contribute to the unique pathophysiological profiles of these disorders. We used a cohort of subjects diagnosed with SCZ, BPD or MDD, and nonpsychiatrically ill control subjects (n = 15/group), together with our bioinformatic 3-pod analysis consisting of full transcriptome pathway analysis, targeted pathway analysis, leading-edge gene analysis and iLINCS perturbagen analysis. We identified altered expression of metabolic pathways in each disorder. Subjects with SCZ displayed downregulation of mitochondrial respiration and nucleotide metabolism pathways. In comparison, we observed upregulation of mitochondrial respiration pathways in subjects with MDD, while subjects with BPD displayed enrichment of pathways involved in carbohydrate metabolism. Several pathways associated with brain metabolism including immune system processes and calcium ion transport were also differentially altered between diagnosis groups. Our findings suggest metabolic pathways, including downregulation of energy metabolism pathways in SCZ and upregulation of energy metabolism pathways in MDD, are uniquely altered in the amygdala in these disorders, which may impact approaches for therapeutic strategies.

Two-thirds of Americans with Alzheimer’s disease are women, indicating a profound variance between the sexes. Variances exist between the sexes in the age and intensity of the presentation, cognitive deficits, neuroinflammatory factors, structural and functional brain changes, as well as psychosocial and cultural circumstances. Herein, we summarize the existing evidence for sexual dimorphism and present the available evidence for these distinctions. Understanding these complexities is critical to developing personalized interventions for the prevention, care, and treatment of Alzheimer’s disease.

Psychiatric disorders like major depressive disorder (MDD), schizophrenia (SCZ), and bipolar disorder (BPD), represent a significant global public health concern. Sex differences in the prevalence and presentation of psychiatric disorders, and the association of a psychiatric diagnosis with increased risk of suicide, are well-established. However, the neurobiology underlying these features of disease are not well understood. Dysfunction of the orbitofrontal cortex (OFC), a brain region responsible for decision-making and sensory processing, has been implicated in psychiatric disorders but remains understudied compared to other frontocortical brain regions. In this study we investigated sexual dimorphism in psychiatric illnesses and suicide by analyzing publicly available OFC transcriptional profiles (RNAseq data obtained from the Stanley Neuropathology Consortium) from individuals with SCZ, BPD, MDD, and non-psychiatric controls (n=15/group). Gene set enrichment analysis (GSEA) revealed significant differences in immune-related processes in male and female comparisons and in psychiatric disorders relative to controls. Analysis of top differentially expressed genes found changes in P2RY12 in males and females who died by suicide. Additionally, downregulation of protein folding processes was observed in female suicide subjects, suggesting an association between dysregulated protein metabolism and suicide. Our results further our understanding of the shared and unique molecular pathways underlying psychiatric disorders and suicide.

The underlying biological mechanisms that contribute to the heterogeneity of major depressive disorder (MDD) presentation remain poorly understood, highlighting the need for a conceptual framework that can explain this variability and bridge the gap between animal models and clinical endpoints. Here, we hypothesize that comparative analysis of molecular data from different experimental systems of chronic stress, and MDD has the potential to provide insight into these mechanisms and address this gap. Thus, we compared transcriptomic profiles of brain tissue from postmortem MDD subjects and from mice exposed to chronic variable stress (CVS) to identify orthologous genes. Ribosomal protein genes (RPGs) were down-regulated, and associated ribosomal protein (RP) pseudogenes were up-regulated in both conditions. A seeded gene co-expression analysis using altered RPGs common between the MDD and CVS groups revealed that down-regulated RPGs homeostatically regulated the synaptic changes in both groups through a RP-pseudogene-driven mechanism. In vitro analysis demonstrated that the RPG dysregulation was a glucocorticoid-driven endocrine response to stress. In silico analysis further demonstrated that the dysregulation was reversed during remission from MDD and selectively responded to ketamine but not to imipramine. This study provides the first evidence that ribosomal dysregulation during stress is a conserved phenotype in human MDD and chronic stress-exposed mouse. Our results establish a foundation for the hypothesis that stress-induced alterations in RPGs and, consequently, ribosomes contribute to the synaptic dysregulation underlying MDD and chronic stress-related mood disorders. We discuss the role of ribosomal heterogeneity in the variable presentations of depression and other mood disorders.

The underlying biological mechanisms that contribute to the heterogeneity of major depressive disorder (MDD) presentation remain poorly understood, highlighting the need for a conceptual framework that can explain this variability and bridge the gap between animal models and clinical endpoints. Here, we hypothesize that comparative analysis of molecular data from different experimental systems of chronic stress and MDD has the potential to provide insight into these mechanisms and address this gap. Thus, we compared transcriptomic profiles of brain tissue from postmortem MDD subjects and from mice exposed to chronic variable stress (CVS) to identify orthologous genes. Ribosomal protein genes (RPGs) were downregulated, and associated RP-pseudogenes were upregulated in both conditions. Analysis across independent cohorts confirmed that this dysregulation was specific to the prefrontal cortex of both species. A seeded gene co-expression analysis using altered RPGs common between the MDD and CVS groups revealed that downregulated RPGs homeostatically regulated the synaptic changes in both groups through a RP-pseudogene-driven mechanism. In-vitro and in-silico analysis further demonstrated that the inverse RPG/RP-pseudogene association was a glucocorticoid-driven endocrine response to stress that was reversed during remission from MDD. This study provides the first evidence that ribosomal dysregulation during stress is a conserved phenotype in human MDD and CVS exposed mouse. Our results establish a foundation for the hypothesis that stress-induced alterations in RPGs and, consequently, ribosomes contribute to the synaptic dysregulation underlying MDD and chronic stress-related mood disorders. We discuss a ribosome-dependent mechanism for the variable presentations of depression and other mood disorders. Significance Statement: The presented study highlights the pressing need for a connection between animal models of depression and clinical endpoints. The lack of concordance between these two areas has hindered our understanding of MDD’s biological underpinnings. The study’s hypothesis that orthologous gene from experimental systems of chronic stress and MDD can bridge this gap is a major advance in this field. The study indicates that dysregulation of ribosomes in the synapse is a common feature in both human MDD and mice exposed to CVS. This dysregulation is a response to endocrine disturbances and is driven by mechanisms that involve pseudogenes. These findings support the hypothesis that stress-induced alterations in RPGs and, consequently, ribosomes may contribute to the variable presentations of depression.

Background: Despite available clinical management strategies, chronic kidney disease (CKD) is associated with severe morbidity and mortality worldwide, which beckons new solutions. Host-microbial interactions with a depletion of Faecalibacterium prausnitzii in CKD are reported. However, the mechanisms about if and how F prausnitzii can be used as a probiotic to treat CKD remains unknown. Methods: We evaluated the microbial compositions in 2 independent CKD populations for any potential probiotic. Next, we investigated if supplementation of such probiotic in a mouse CKD model can restore gut-renal homeostasis as monitored by its effects on suppression on renal inflammation, improvement in gut permeability and renal function. Last, we investigated the molecular mechanisms underlying the probiotic-induced beneficial outcomes. Results: We observed significant depletion of Faecalibacterium in the patients with CKD in both Western (n=283) and Eastern populations (n=75). Supplementation of F prausnitzii to CKD mice reduced renal dysfunction, renal inflammation, and lowered the serum levels of various uremic toxins. These are coupled with improved gut microbial ecology and intestinal integrity. Moreover, we demonstrated that the beneficial effects in kidney induced by F prausnitzii -derived butyrate were through the GPR (G protein-coupled receptor)-43. Conclusions: Using a mouse CKD model, we uncovered a novel beneficial role of F prausnitzii in the restoration of renal function in CKD, which is, at least in part, attributed to the butyrate-mediated GPR-43 signaling in the kidney. Our study provides the necessary foundation to harness the therapeutic potential of F prausnitzii for ameliorating CKD.

Antipsychotic drugs (APDs) are effective in treating positive symptoms of schizophrenia (SCZ). However, they have a substantial impact on postmortem studies. As most cohorts lack samples from drug-naive patients, many studies, rather than understanding SCZ pathophysiology, are analyzing the drug effects. We hypothesized that comparing SCZ-altered and APD-influenced signatures derived from the same cohort can provide better insight into SCZ pathophysiology. For this, we performed LCMS-based proteomics on dorsolateral prefrontal cortex (DLPFC) samples from control and SCZ subjects and used statistical approaches to identify SCZ-altered and APD-influenced proteomes, validated experimentally using independent cohorts and published datasets. Functional analysis of both proteomes was contrasted at the biological-pathway, cell-type, subcellular-synaptic, and drug-target levels. In silico validation revealed that the SCZ-altered proteome was conserved across several studies from the DLPFC and other brain areas. At the pathway level, SCZ influenced changes in homeostasis, signal-transduction, cytoskeleton, and dendrites, whereas APD influenced changes in synaptic-signaling, neurotransmitter-regulation, and immune-system processes. At the cell-type level, the SCZ-altered and APD-influenced proteomes were associated with two distinct striatum-projecting layer-5 pyramidal neurons regulating dopaminergic-secretion. At the subcellular synaptic level, compensatory pre- and postsynaptic events were observed. At the drug-target level, dopaminergic processes influenced the SCZ-altered upregulated-proteome, whereas nondopaminergic and a diverse array of non-neuromodulatory mechanisms influenced the downregulated-proteome. Previous findings were not independent of the APD effect and thus require re-evaluation. We identified a hyperdopaminergic cortex and drugs targeting the cognitive SCZ-symptoms and discussed their influence on SCZ pathology in the context of the cortico-striatal pathway.