Journal of Molecular Neuroscience最新文献

It is well known that the development of neurodegeneration, and especially Alzheimer’s disease (AD), is often accompanied by impaired olfaction which precedes memory loss. A neuropeptidase neprilysin (NEP)—a principal amyloid-degrading enzyme in the brain—was also shown to be involved in olfactory signalling. Previously we have demonstrated that 5xFAD mice develop olfactory deficit by the age of 6 months which correlated with reduced NEP expression in the brain areas involved in olfactory signalling. The aim of this study was to analyse the effect of administration of a histone deacetylase inhibitor, valproic acid (VA), to adult 5xFAD mice on their olfaction and memory as well as on brain morphology and NEP expression in the parietal cortex (PC) and hippocampus (Hip). The data obtained demonstrated that administration of VA to 7-month-old mice (200 mg/kg of body weight) for 28 days resulted in improvement of their memory in the Morris water maze as well as olfaction in the odor preference and food search tests. This correlated with increased expression of NEP in the PC and Hip as well as a reduced number of amyloid plaques in these brain areas. This strongly suggests that NEP can be considered an important therapeutic target not only in AD but also in olfactory loss.

Specific learning disorder (SLD) is prevalent worldwide and is a complex disorder with variable symptoms and significant differences among individuals. Epigenetic markers may alter susceptibility to neurodevelopmental disorders (NDDs). Aberrant expression of protein-coding (mRNA) genes in this pathology shows that the detection of epigenetic molecular biomarkers is of increasing importance in the diagnosis and treatment of individuals with SLD. We compared gene expression level of dyslexia susceptibility 1 candidate gene 1 (DYX1C1), dyslexia-associated protein KIAA0319 (KIAA0319), and roundabout guidance receptor 1 (ROBO1) between children with SLD and healthy children by performing quantitative polymerase chain reaction (qPCR). In addition, we evaluated these gene expressions of severe children with SLD compared to non-severe and male SLD children compared to females. The expression of the DYX1C1, KIAA0319, and ROBO1 genes was statistically significantly upregulated in children with SLD (P < 0.05*). DYX1C1 was also upregulated in severe SLD children (P = 0.03*). In addition, KIAA0319 and ROBO1 genes were differentially expressed in male SLD children compared to females (P < 0.05*). Furthermore, we found that DYX1C1 and ROBO1 genes significantly affect the likelihood of the SLD (respectively, P < 0.001** and P = 0.007*). We expect that the findings provided from this study may contribute to the determination expression level of the relevant genes in the diagnosis, prognosis, and treatment of SLD. In addition, our findings could be a guide for future epigenetics studies on the use of the DYX1C1, KIAA0319, and ROBO1 in therapeutic applications in the SLD.

Regeneration of the sciatic nerve is a sophisticated process that involves the interplay of several signaling pathways that orchestrate the cellular responses critical to regeneration. Among the key pathways are the mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K)/AKT, cyclic adenosine monophosphate (cAMP), and Janus kinase/signal transducers and transcription activators (JAK/STAT) pathways. In particular, the cAMP pathway modulates neuronal survival and axonal regrowth. It influences various cellular behaviors and gene expression that are essential for nerve regeneration. MAPK is indispensable for Schwann cell differentiation and myelination, whereas PI3K/AKT is integral to the transcription, translation, and cell survival processes that are vital for nerve regeneration. Furthermore, GTP-binding proteins, including those of the Ras homolog gene family (Rho), regulate neural cell adhesion, migration, and survival. Notch signaling also appears to be effective in the early stages of nerve regeneration and in preventing skeletal muscle fibrosis after injury. Understanding the intricate mechanisms and interactions of these pathways is vital for the development of effective therapeutic strategies for sciatic nerve injuries. This review underscores the need for further research to fill existing knowledge gaps and improve therapeutic outcomes.

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Mitochondria play a pivotal role in cellular metabolism, energy production, and apoptotic signaling, making mitophagy, the selective degradation of damaged mitochondria, crucial for mitochondrial health. Dysregulation of mitophagy has been implicated in various neuroendocrinopathies, yet the mechanisms linking these processes remain poorly understood. This review aims to explore the intersection between mitophagy and neuroendocrinopathy, addressing the critical gaps in knowledge regarding how mitochondrial dysfunction may contribute to the pathophysiology of neuroendocrine disorders. We conducted a comprehensive literature review of studies published on mitophagy and neuroendocrinopathies, focusing on data that elucidate the pathways involved and the clinical implications of mitochondrial health in neuroendocrine contexts. Our findings indicate that altered mitophagy may lead to the accumulation of dysfunctional mitochondria, contributing to neuroendocrine dysregulation. We present evidence linking impaired mitochondrial clearance to disease models of conditions such as metabolic syndrome, depression, and stress-related disorders, highlighting the potential for therapeutic interventions targeting mitophagy. While significant advances have been made in understanding mitochondrial biology, the direct interplay between mitophagy and neuroendocrinopathies remains underexplored. This review underscores the necessity for further research to elucidate these connections, which may offer novel insights into disease mechanisms and therapeutic strategies for treating maladaptive neuroendocrine responses.

Traumatic brain injury (TBI) is caused by an external mechanical force to the head, resulting in abnormal brain functioning and clinical manifestations. Antisecretory factor (AF16) is a potential therapeutic agent for TBI treatment due to its ability to inhibit fluid secretion and decrease inflammation, intracranial pressure, and interstitial fluid build-up, key hallmarks presented in TBI. Here, we investigated the effect of AF16 in an in vitro model of neuronal injury, as well as its impact on key components of the autophagy pathway and mitochondrial dynamics. N2A^wt cells were treated with AF16, injured using a scratch assay, and analysed using confocal microscopy, correlative light and electron microscopy (CLEM), flow cytometry, and western blotting. Our results reveal that AF16 enhances autophagy activity, regulates mitochondrial dynamics, and provides protection as early as 6 h post-injury. Fluorescently labelled AF16 was observed to localise to lysosomes and the autophagy compartment, suggesting a role for autophagy and mitochondrial quality control in conferring AF16-associated neuronal protection. This study concludes that AF16 has potential as a therapeutic agent for TBI treatment through is regulation of autophagy and mitochondrial dynamics.

Physical activity has been demonstrated to improve cognitive function, thereby preventing/slowing neurodegenerative diseases (NDs). Biological responses to physical activity and vulnerabilities to NDs are emerging to be gender-related. Herein, known ND-associated markers (β-amyloid, tau, α-synuclein), main sex steroid hormones, antioxidant responses, and key gene transcription modulators were evaluated in the blood of physically active and sedentary women and men. In our hands, females presented higher basal erythrocytes β-amyloid and α-synuclein amounts than males. Regular physical activity was able to significantly reduce the erythrocyte content of β-amyloid in females and the tau levels in males, suggesting that these differences may be mediated by organizational actions of sex steroid hormones during development. Furthermore, despite a comparable plasma antioxidant capability (AOC) between males and females, in the latter group, physical activity significantly enhances AOC versus peroxynitrite radicals only. Finally, regular physical activity modulated the levels of transcription factor Nrf2 in erythrocytes, as well as the plasma concentration of the microRNA miR-195 and miR-153, suggesting the promotion of antioxidant/autophagic processes associated with ND-related proteins. Overall, these results could shed light on how cerebral adaptations to physical activity differ between males and females, especially with regard to blood accumulation of ND proteins and mechanisms of antioxidant responses to regular exercise.

With the persistent challenge that epilepsy presents to therapeutic avenues, the study seeks to decipher the effects of the ketogenic diet (KD) on gut microbiota and subsequent epileptic outcomes. Mouse fecal samples from distinct KD and control diet (CD) cohorts underwent 16S rRNA sequencing. Differential genes of epileptic mice under these diets were sourced from the GEO database. The study melded in vivo and in vitro techniques to explore the nuanced interactions between KD, gut microbiota, and hippocampal TRHR dynamics. The KD regimen was found to result in a notable reduction in gut microbiota diversity when compared to the CD groups. Distinctive microbial strains, which are hypothesised to interact with epilepsy through G protein-coupled receptors, were spotlighted. In vivo, explorations affirmed that gut microbiota as central to KD’s anti-epileptic efficacy. Of 211 distinguished genes, the neuroactive ligand-receptor interaction pathway was underscored, particularly emphasizing TRHR and TRH. Clinical observations revealed a surge in hippocampal TRHR and TRH expressions influenced by KD, mirroring shifts in neuronal discharges. The KD, leveraging gut microbiota alterations, amplifies hippocampal TRHR expression. This finding provides a novel intervention strategy to reduce seizures.

Chromodomain helicase DNA-binding 8 (CHD8) is a gene that poses a high risk for autism spectrum disorder (ASD) and neurological development delay. Nevertheless, the impact of CHD8 haploinsufficiency on both hippocampus neurogenesis and behavior remains uncertain. Here, we performed behavioral assessments on male and female CHD8 heterozygous mice. The study discovered that both male and female CHD8 heterozygous mice displayed an impairment in preference for social novelty. Concurrently, CHD8 heterozygous mice exhibited anxiety-like behavior. However, its cognitive capacity for learning and memory is within the expected range. Furthermore, we discovered a reduction in the number of both immature and mature new neurons in mice with CHD8 heterozygous, resulting in an impeded neurogenesis process in the hippocampus. Taken together, our findings indicate that CHD8 plays a crucial role in the regulation of hippocampal neurogenesis, and further suggest that ASD-like behaviors observed in CHD8 heterozygous mice may be associated with disruptions in hippocampal neurogenesis.

Although brain amyloid-β (Aβ) peptide buildup is the main cause of Alzheimer’s disease (AD), mitochondrial abnormalities can also contribute to the illness’s development, as either a primary or secondary factor, as programmed cell death and efficient energy generation depend on the proper operation of mitochondria. As a result, non-coding RNAs (ncRNAs) may play a crucial role in ensuring that nuclear genes related to mitochondria and mitochondrial genes function normally. Interestingly, a significant number of recent studies have focused on the impact of ncRNAs on the expression of nucleus and mitochondrial genes. Additionally, researchers have proposed some intriguing therapeutic approaches to treat and reduce the severity of AD by adjusting the levels of these ncRNAs. The goal of this work was to consolidate the existing knowledge in this field of study by systematically investigating ncRNAs, with a particular emphasis on microRNAs (miRNAs), long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), and small nucleolar RNAs (snoRNAs). Therefore, the impact and processes by which ncRNAs govern mitochondrial activity in the onset and progression of AD are thoroughly reviewed in this article. Collectively, the effects of ncRNAs on physiological and molecular mechanisms associated with mitochondrial abnormalities that exacerbate AD are thoroughly reviewed in the current research, while also emphasizing the relationship between disturbed mitophagy in AD and ncRNAs.

Hearing loss (HL) is one of the most common health problems worldwide. Autosomal recessive non-syndromic sensorineural hearing loss (ARNSHL) represents a large portion of congenital hereditary HL. Our study was conducted on 13 patients from 13 unrelated families. The majority of patients presented with congenital severe to profound bilateral sensorineural HL. All patients were subjected to detailed family history and three-generation pedigree analysis to exclude any environmental cause and to ensure an autosomal recessive mode of inheritance. Molecular analysis was performed using the whole exome sequencing (WES) technique for the recruited patients. Three variants in the MYO7A and OTOF genes were reported for the first time in patients with ARNSHL (one nonsense, one frameshift, and one splice variant). Ten previously reported variants were detected in seven genes (GJB2, MYO15A, BSND, OTOF, CDH23, SLC26A4, and TMIE). They varied between missense, nonsense, frameshift, and splice variants. This study expands the molecular spectrum of two types of autosomal recessive deafness (types 2 and 9).