Σάββατο, 13 Ιουλίου 2019

Molecular Neuroscience

CADASIL with Atypical Clinical Symptoms, Magnetic Resonance Imaging, and Novel Mutations: Two Case Reports and a Review of the Literature


Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary microangiopathy with adult onset caused by a missense mutation in the NOTCH3 gene in chromosome 19p13. It presents with autosomal dominant arteriopathy, subcortical infarctions, and leukoencephalopathy. Its common clinical presentations are seen as recurrent strokes, migraine or migraine-like headaches, progressive dementia, pseudobulbar paralysis, and psychiatric conditions. Two patients with CADASIL syndrome, whose diagnosis was made based on clinical course, age of onset, imaging findings, and genetic assays in the patients and family members, are presented here because of new familial polymorphisms. The first patient, with cerebellar and psychotic findings, had widespread non-confluent hyperintense lesions as well as moderate cerebellar atrophy in cranial magnetic resonance scanning. The other patient, with headache, dizziness, and forgetfulness, had gliotic lesions in both cerebral hemispheres. CADASIL gene studies revealed a new polymorphism in exon 33 in the first patient. In the other patient, the NOTCH3 gene was identified as a new variant of p.H243P (c.728A > C heterozygous). By reporting a family presenting with various clinical symptoms in the presence of new polymorphisms, we emphasize that CADASIL syndrome may present with various clinical courses and should be considered in differential diagnoses.

Impact of Auditory Integration Therapy (AIT) on the Plasma Levels of Human Glial Cell Line–Derived Neurotrophic Factor (GDNF) in Autism Spectrum Disorder


Neurotrophic factors, including the glial cell line–derived neurotrophic factor (GDNF), are of importance for synaptic plasticity regulation, intended as the synapses' ability to strengthen or weaken their responses to differences in neuronal activity. Such plasticity is essential for sensory processing, which has been shown to be impaired in autism spectrum disorder (ASD). This study is the first to investigate the impact of auditory integration therapy (AIT) of sensory processing abnormalities in autism on plasma GDNF levels. Fifteen ASD children, aged between 5 and 12 years, were enrolled and underwent the present research study. AIT was performed throughout 10 days with a 30-min session twice a day. Before and after AIT, Childhood Autism Rating Scale (CARS), Social Responsiveness Scale (SRS), and Short Sensory Profile (SSP) scores were calculated, and plasma GDNF levels were assayed by an EIA test. A substantial decline in autistic behavior was observed after AIT in the scaling parameters used. Median plasma GDNF level was 52.142 pg/ml before AIT. This level greatly increased immediately after AIT to 242.05 pg/ml (P < 0.001). The levels were depressed to 154.00 pg/ml and 125.594 pg/ml 1 month and 3 months later, respectively, but they were still significantly higher compared with the levels before the treatment (P = 0.001, P = 0.01, respectively). There was an improvement in the measures of autism severity as an effect of AIT which induced the up-regulation of GDNF in plasma. Further research, on a large scale, is needed to evaluate if the cognitive improvement of ASD children after AIT is related or not connected to the up-regulation of GDNF.

Identification of Important Invasion-Related Genes in Non-functional Pituitary Adenomas


Non-functioning pituitary adenomas (NFPAs) are locally invasive with high morbidity. The objective of this study was to diagnose important genes and pathways related to the invasiveness of NFPAs and gain more insights into the underlying molecular mechanisms of NFPAs. The gene expression profiles of GSE51618 were downloaded from the Gene Expression Omnibus database with 4 non-invasive NFPA samples, 3 invasive NFPA samples, and 3 normal pituitary gland samples. Differentially expressed genes (DEGs) are screened between invasive NFPA samples and normal pituitary gland samples, followed by pathway and ontology (GO) enrichment analyses. Subsequently, a protein–protein interaction (PPI) network was constructed and analyzed for these DEGs, and module analysis was performed. In addition, a target gene–miRNA network and target gene–TF (transcription factor) network were analyzed for these DEGs. A total of 879 DEGs were obtained. Among them, 439 genes were upregulated and 440 genes were downregulated. Pathway enrichment analysis indicated that the upregulated genes were significantly enriched in cysteine biosynthesis/homocysteine degradation (trans-sulfuration) and PI3K-Akt signaling pathway, while the downregulated genes were mainly associated with docosahexaenoate biosynthesis III (mammals) and chemokine signaling pathway. GO enrichment analysis indicated that the upregulated genes were significantly enriched in animal organ morphogenesis, extracellular matrix, and hormone activity, while the downregulated genes were mainly associated with leukocyte chemotaxis, dendrites, and RAGE receptor binding. Subsequently, ESR1, SOX2, TTN, GFAP, WIF1, TTR, XIST, SPAG5, PPBP, AR, IL1R2, and HIST1H1C were diagnosed as the top hub genes in the upregulated and downregulated PPI networks and modules. In addition, HS3ST1, GPC4, CCND2, and SCD were diagnosed as the top hub genes in the upregulated and downregulated target gene–miRNA networks, while CISH, ISLR, UBE2E3, and CCNG2 were diagnosed as the top hub genes in the upregulated and downregulated target gene–TF networks. The new important DEGs and pathways diagnosed in this study may serve key roles in the invasiveness of NFPAs and indicate more molecular targets for the treatment of NFPAs.

From the Editors Desk: Angela Zawacki-Downing Writing to Professor Illana Gozes, Editor-in-Chief Journal of Molecular Neuroscience—Speaking from a Mother's Heart, AD's ADNP Syndrome

Application of Single-Nucleotide Polymorphisms in the Diagnosis of Autism Spectrum Disorders: A Preliminary Study with Artificial Neural Networks


Autism spectrum disorder (ASD) includes different neurodevelopmental disorders characterized by deficits in social communication, and restricted, repetitive patterns of behavior, interests or activities. Based on the importance of early diagnosis for effective therapeutic intervention, several strategies have been employed for detection of the disorder. The artificial neural network (ANN) as a type of machine learning method is a common strategy. In the current study, we extracted genomic data for 487 ASD patients and 455 healthy individuals. All individuals were genotyped in certain single-nucleotide polymorphisms within retinoic acid-related orphan receptor alpha (RORA), gamma-aminobutyric acid type A receptor beta3 subunit (GABRB3), synaptosomal-associated protein 25 (SNAP25) and metabotropic glutamate receptor 7 (GRM7) genes. Subsequently, we used the "Keras" package to create and train the ANN model. For cross-validation, samples were divided into ten folds. In the training process, initially, the first fold was preserved for validation and the other folds were used to train the model. The validation fold was then used to evaluate model performance. The k-fold cross-validation method was used to ensure model generalizability and to prevent overfitting. Local interpretable model-agnostic explanations (LIME) were applied to explain model predictions at the data sample level. The output of loss function was evaluated in the training process for each fold in the k-fold cross-validation model. Finally, the number of losses was reduced to less than 0.6 after 200 epochs (except in two cases). The accuracy, sensitivity and specificity of our model were 73.67%, 82.75% and 63.95%, respectively. The area under the curve (AUC) was 80.59. Consequently, in the current study, we propose an ANN-based method for differentiating ASD status from healthy status with adequate power.

14-3-3/Tau Interaction and Tau Amyloidogenesis


The major function of microtubule-associated protein tau is to promote microtubule assembly in the central nervous system. However, aggregation of abnormally phosphorylated tau is a hallmark of tauopathies. Although the molecular mechanisms of conformational transitions and assembling of tau molecules into amyloid fibril remain largely unknown, several factors have been shown to promote tau aggregation, including mutations, polyanions, phosphorylation, and interactions with other proteins. 14-3-3 proteins are a family of highly conserved, multifunctional proteins that are mainly expressed in the central nervous system. Being a scaffolding protein, 14-3-3 proteins interact with tau and regulate tau phosphorylation by bridging tau with various protein kinases. 14-3-3 proteins also directly regulate tau aggregation via specific and non-specific interactions with tau. In this review, we summarize recent advances in characterization of tau conformation and tau/14-3-3 interaction. We discuss the connection between 14-3-3 binding and tau aggregation with a special emphasis on the regulatory role of 14-3-3 on tau conformation.

The Mechanism of Rap1 Regulates N-cadherin to Control Neuronal Migration


Rap1 and N-cadherin regulate glia-independent translocation of cortical neurons. It remains unclear how Rap1 regulates N-cadherin-mediated neuronal migration. Here, we overexpressed Rap1gap in mouse brains (embryonic day 16) to inactivate Rap1, and observed that neurons did not migrate to the outer layer. We confirmed that Rap1 was involved in the regulation of late neurons in vivo. Rap1gap overexpression and Rap1 suppression in CHO cells decreased the expression of cytoskeletal proteins such as tubulin. Changes in the expression of cell morphology regulators, such as N-cadherin and β-catenin, were also observed. Inhibition of N-cadherin in mouse brains prevented neuronal migration to the outer layer. The morphology of CHO cells was changed after overexpression of Rap1gap. We propose that Rap1 regulates the expression of N-cadherin during embryonic development, which affects β-catenin expression. Beta-catenin in turn regulates cytoskeletal protein expression, ultimately affecting neuronal morphology and migration.

Adult-Onset Hypothyroidism Alters the Metaplastic Properties of Dentate Granule Cells by Decreasing Akt Phosphorylation


The expression of homosynaptic long-term depression (LTD) governs the subsequent induction of long-term potentiation (LTP) at hippocampal synapses. This process, called metaplasticity, is associated with a transient increase in the levels of several kinases, such as extracellular signal-regulated protein kinases 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK), and Akt kinase. It has been increasingly realized that the chemical changes in the hippocampus caused by hypothyroidism may be the key underlying causes of the learning deficits, memory loss, and impaired LTP associated with this disease. However, the functional role of thyroid hormones in the "plasticity of synaptic plasticity" has only begun to be elucidated. To address this issue, we sought to determine whether the administration of 6-n-propyl-2-thiouracil (PTU) alters the relationship between priming and the induction of subsequent LTP and related signaling molecules. The activation of ERK1/2, JNK, and Akt was measured in the hippocampus at least 95 min after priming onset. We found that priming stimulation at 5 Hz for 3 s negatively impacted the induction of LTP by subsequent tetanic stimulation in hypothyroid animals, as manifested by a more rapid decrease in the fEPSP slope and population spike amplitude. This phenomenon was accompanied by lower levels of phosphorylated Akt in the surgically removed hippocampus of the hypothyroid rats compared to the euthyroid rats. The metaplastic response and the expression of these proteins in the 1-Hz-primed hippocampus were not different between the two groups. These observations suggest that decreased PI3K/Akt signaling may be involved in the compromised metaplastic regulation of LTP observed in hypothyroidism, which may account for the learning difficulties/cognitive impairments associated with this condition.

TP53 Polymorphism Contributes to the Susceptibility to Bipolar Disorder but Not to Schizophrenia in the Chinese Han Population


TP53 has been reported to be involved in diverse neurological processes related to the pathogenesis of psychosis. In this study, we aim to determine the association of TP53 polymorphisms, rs1042522 and rs17879353, with the susceptibility to schizophrenia (SCZ) or bipolar disorder (BD) in Chinese Han population. A total of 548 SCZ patients, 512 BD patients, and 598 healthy controls were recruited. Genotyping was conducted through Sequenom MassARRAY technology platform. The quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect TP53 expression level. Results revealed that the allele frequency and genotype distribution of rs1042522 within BD patients were significantly different from those of the controls. Rs1042522 was significantly associated with BD risk under diverse genetic models. However, no significant association was found for rs17879353 and BD risk and for rs1042522 and rs17879353 and SCZ risk. TP53 expression was significantly increased in SCZ patients and BD patients compared with that in the controls but was significantly decreased in BD patients with CC genotype of rs1042522 compared with that in other BD patients with either CG or GG genotype. In summary, we observed for the first time that rs1042522 is significantly associated with BD risk in the Chinese Han population. The increased TP53 expression might affect the occurrence of BD and SCZ, and rs1042522 might affect the progress of BD by disturbing gene expression.

Myeloid-Related Protein 8/14 Participates in the Progression of Experimental Pneumococcal Meningitis by Augmentation of Inflammation


It has been reported that myeloid-related protein 8/14 (MRP8/14) participates in the progression of inflammation after release from neutrophils and monocytes. This study aimed to clarify the mechanism(s) of the MRP8/14-augmented inflammatory response in mice with pneumococcal meningitis. Streptococcus pneumoniae (SP) meningitis was established by intracerebral injection of SP suspension. Balb/c mice were randomly divided into four groups and received the following injections: phosphate-buffer saline (PBS), MRP8/14 alone, SP alone, and SP plus MRP8/14. At 6 h, 24 h and 48 h postinfection, the clinical disease status was measured by the modified neurological severity score test, body weight loss and degree of cerebral edema; mice were anaesthetized, blood samples and brain samples were collected and brain inflammation was detected by haematoxylin and eosin (HE) staining; tumour necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), C-reactive protein (CRP) and monocyte chemoattractant protein-1 (MCP-1) levels in serum and brain homogenates were assessed by an enzyme-linked immunosorbent assay (ELISA), and the mRNA levels of the above cytokines in brain homogenates were measured by polymerase chain reaction (PCR); and the expression of nuclear factor-kappa B (NF-κB) p65 in brain tissues was determined by immunohistochemical assay. In this study, we identified that MRP8/14 substantially augmented the SP-stimulated inflammatory response, aggravated clinical disease status and exacerbated SP-induced brain edema in a murine model of pneumococcal meningitis. Exogenous administration of MRP8/14 significantly enhanced mRNA and protein expression of the proinflammatory cytokines and chemokines TNF-α, CRP, IL-6 and MCP-1 in brain homogenates and serum from mice with pneumococcal meningitis, which may be related to the NF-κB signalling pathway. We further found that MRP8/14 strongly augmented SP-induced phosphorylation of NF-κB p65 in brain tissue slices from the same model. In conclusion, our results indicated that MRP8/14 augmented the inflammatory response in mice with pneumococcal meningitis and contributed to the development of disease, which was probably through NF-κB signalling pathway activation.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos

Δεν υπάρχουν σχόλια:

Δημοσίευση σχολίου

Δημοφιλείς αναρτήσεις