Frontiers in Molecular Neuroscience最新文献

Amyotrophic lateral sclerosis (ALS) is characterized by the progressive loss of upper and lower motor neurones, leading to muscle wasting, paralysis and respiratory failure. Pathological cytoplasmic aggregation of the RNA-binding protein transactive response DNA-binding protein 43 (TDP-43) protein occurs in neural tissues in ~97% of all ALS cases, and is also observed in skeletal muscle. Cytoplasmic aggregation of TDP-43 is believed to contribute to ALS pathogenesis; however, its precise mechanistic role/s continues to elude the field. This mini review explores the potential role and regulation of two TDP-43-associated RNA-protein assemblies, stress granules (SGs) and myogranules (MGs). We review the current understanding of SG and MG formation and their potential role in ALS-related neurodegeneration and muscle pathology. We also highlight limitations and strengths and suggest future directions for research.

Introduction: Neuropathic pain (NP) is a kind of common and intractable chronic pain. Hydrogen (H₂)-rich water exhibited protective effects in NP by intrathecal injection, drinking, and intraperitoneal injection. The nanobubble H2-dissolved water (NHW) is a solution that contains H₂ bubbles and H₂ in lysis state. Therefore, this study aimed to observe the effects of ultrasound-guided local injection with NHW in the model of NP, and try to find its possible mechanism.

Methods: The rat sciatic nerve was ligated to establish chronic constriction injury (CCI)-induced NP model. The CCI rats received NHW at low or high concentrations 1 or 3 times (n = 6). During the experiment, the paw withdrawal thresholds (PWT) and paw withdrawal latency (PWL) were detected. At 14 days after CCI, the organizational structure of nerve, inflammatory response, and oxidative stress damage were measured. Additionally, the Nrf2/HO-1 and sulfiredoxin-1 were also detected by western blotting and RT-PCR.

Results: Compared with low concentration, in the high concentration group, the PWT and PWL were attenuated on Day 1, 3, 5, 7, and 14 after CCI (p < 0.05). On Day 14, nerve injury, inflammatory response, and oxidative stress injury were relieved significantly in high concentration than at low concentration, and the effect was greater at multiple doses (3 times) at high concentrations (p < 0.05), as were the increase in the protein and mRNA levels of Nrf2/HO-1 and sulfiredoxin-1.

Conclusion: Ultrasound-guided early local injection of NHW attenuated sciatic nerve injury, alleviated mechanical allodynia and thermal hyperalgesia and inhibited inflammation and oxidative stress damage via the Nrf2/HO-1-sulfiredoxin1 pathway in a rat model of CCI.

Introduction: Alzheimer's disease (AD) is characterized by the accumulation of amyloid-beta (Aβ) peptides, which contribute to synaptic dysfunction, neuronal toxicity, and gene expression alterations. In a previous study, we identified a phage displaying a peptide that selectively interacts with Aβ autoantibodies.

Methods: Here, we assessed whether this phage also directly interacts with Aβ, as predicted through bioinformatic analyses. We evaluated its functional effects in a neuronal cell line exposed to Aβ and performed transcriptomic profiling by RNA sequencing.

Results: We demonstrate that the phage directly interacts with Aβ, consistent with bioinformatic predictions. Functionally, the phage protected the neuronal cell line from Aβ-induced toxicity. RNA sequencing revealed that the phage prevented Aβ-induced alterations in the expression of 1,819 genes, suggesting a role in modulating Aβ-associated metabolic changes.

Discussion: These findings highlight the therapeutic potential of phage-displayed peptides in counteracting Aβ toxicity and restoring cellular homeostasis, laying a foundation for future investigations into phage-based interventions for AD.

The postmenopausal period is associated with an increased tendency to gain weight. This may be due to disturbances in appetite regulation, mainly in the hypothalamus and nutritional behaviors, as well as persistent neuroinflammation resulting from estrogen deficiency. Research indicates that physical activity may counteract estrogen deficiency by improving hypothalamic regulation of appetite and inflammation, thereby promoting better energy balance and decreasing the risk of weight gain after menopause. We investigated whether voluntary wheel running (VWR) impacts factors related to appetite, energy homeostasis, and neuroinflammatory changes induced by ovariectomy (OVX). Thus, 13-month-old female mice underwent OVX, creating a comprehensive model of reproductive aging in females. Ovariectomized (OVX-VWR) and sham-operated (SHAM-VWR) mice were subjected to 6 weeks of VWR. The control sedentary groups (SHAM-SED, OVX-SED) were housed with immobilized wheels. The body mass, food and water intake, and daily running activity were recorded. Hypothalamic and serum samples were collected to examine the expression levels of genes, proteins, and hormones related to appetite regulation and neuroinflammation processes. OVX mice gained weight most excessively and showed reduced running activity. OVX downregulated the ERα/ERβ ratio, and VWR increased ERβ expression. VWR increased Lepr and Cckar expression in the sham-operated group. VWR has an impact on hypothalamic neuroinflammation regardless of ovarian status, through changes in expression of NLRP3, pro-IL-18, TLR4, pro-caspase 1, Il-1b, and Il-18. OVX in middle-aged mice altered body weight and energy metabolism, but did not affect food intake. VWR modulated hypothalamic appetite-regulating factors-changes not seen in OVX females-and elicited a comparable neuroinflammatory response in the hypothalamus of both SHAM- and OVX-operated mice.

Introduction: Sciatica is a prevalent and highly debilitating condition that is clinically characterized by pain radiating along the distribution of the sciatic nerve. Despite its common occurrence, the progression of early sciatica remains not yet fully elucidated. The aim of this study is to explore the potential molecular mechanism underlying early-stage sciatica progression.

Methods: A total of 20 rats were collected, with 9 in the control group and 11 rats in the chronic constriction injury (CCI) model group. The sciatic nerve tissues of rats were collected at three time points 1, 3, and 7 days post surgery. Protein microarray was used to detect the expression levels of 27 cytokines in sciatic nerve tissues at different times. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were used for functional and pathway analysis of the differentially expressed proteins (DEPs). ELISA was used to detect the levels of chemokine CINC-2 and neurotrophic growth factors (CNTF).

Results: A total of 11 proteins showed significant differential expression between the CCI and control groups at all three time points (days 1, 3, and 7) after sciatic nerve injury. Specifically, Cytokine-Induced Neutrophil Chemoattractant-2 (CINC-2), Cytokine-Induced Neutrophil Chemoattractant-3 (CINC-3), Lipopolysaccharide-Induced CXC chemokine (LIX), Lymphocyte-Selectin (L-Selectin), Platelet-Derived Growth Factor-AA (PDGF-AA), Interleukin-1 alpha (IL-1α), Interleukin-6 (IL-6), Tissue Inhibitor of Metalloproteinase-1 (TIMP-1), and beta-Nerve Growth Factor (β-NGF) were significantly upregulated (p < 0.05), whereas the neurotrophic-related protein CNTF was significantly downregulated (p < 0.05). KEGG pathway analysis revealed that these DEPs were primarily enriched in key inflammatory signaling pathways, including the JAK-STAT, Cytokine-cytokine receptor interaction, Chemokine, Tumor Necrosis Factor (TNF), NOD-like receptor, and NF-kappa B signaling pathways. GO analysis indicated their involvement in biological processes such as immune response and cellular chemotaxis. Protein function analysis further confirmed the close correlation of these DEPs with cellular recognition and neuroinflammation. Additionally, ELISA validation showed that the key protein CINC-2 was upregulated and CNTF was significantly downregulated in the early CCI group.

Discussion: The progression of early sciatic is closely associated with neuroinflammation triggered by the overexpression of inflammatory factors and nerve dysfunction mediated by neurotrophic-related proteins.

Introduction: Parkinson's disease (PD) is a chronic neurodegenerative disorder characterized by loss of dopaminergic neurons and α-synuclein aggregation in the midbrain. One proposed mechanism in PD pathogenesis is endoplasmic reticulum (ER) stress followed by activation of the unfolded protein response (UPR). The UPR consists of three main branches, among which the protein kinase RNA-like ER kinase (PERK) and inositol-requiring enzyme 1 (IRE1) contribute to pro-apoptotic signaling by inducing C/EBP homologous protein (CHOP) and c-Jun N-terminal kinase (JNK), respectively.

Methods: This study investigates the neuroprotective potential of selective inhibition of PERK/CHOP and IRE1/JNK signaling against rotenone (ROT)-induced toxicity in differentiated SH-SY5Y cells, an in vitro model of PD. For this purpose, the inhibitors of mentioned UPR pathways AMG44 and JNK V were applied, and their biological effect was examined in terms of cell viability, morphology, cell death, oxidative stress level, gene and protein expression profiles.

Results: Exposure to ROT significantly decreased cell viability, disrupted cell morphology, induced reactive oxygen species generation, apoptosis, necrosis, and affected the expression of UPR-related factors, indicative of ER stress, oxidative damage and cell death. Treatment with AMG44 and JNK V significantly prevented or reversed these changes, and the underlying mechanism involved altered expression of the specific ER stress-related markers. Moreover, inhibition of one of the UPR pathways influenced the other, highlighting the crosstalk between PERK/CHOP and IRE1/JNK branches in ROT-induced neurotoxicity.

Conclusion: Targeting PERK- and IRE1-dependent pathways contributes to neuroprotection in ROT-based PD model, which indicates the potential of UPR inhibitors as therapeutic agents for PD.

Glycosylation, a crucial post-translational modification, involves the covalent attachment of monosaccharides or oligosaccharides to proteins. This process significantly influences protein stability and function. Within the nervous system, glycosylation regulates key processes including neuronal differentiation, migration, synapse formation, and neurotransmitter release and signaling. Its proper functioning is essential for maintaining neuronal homeostasis and reducing the risk of neurological disorders. Understanding the specific mechanisms by which glycosylation impacts the central nervous system is therefore essential for developing novel therapeutic strategies. This review focuses on the roles of three major glycosylation types-N-glycosylation, O-glycosylation, and O-GlcNAcylation-in the pathogenesis of central nervous system disorders.

The granin gene family of neuropeptides functions as peptide neurotransmitters in the brain for the regulation of neural functions that regulate behaviors. Granins are involved in regulating cognition, memory, depression, aggression, stress, energy expenditure, inflammation, and related. Development of the human brain involves formation of synapses and their spectrum of neurotransmitters to establish neural connections that are required for brain functions. Therefore, the goal of this study was to analyze the gene expression profiles of the granin neurotransmitter genes during human brain development at prenatal, infancy, childhood, adolescence, and adult stages. Granin gene expression in brain development was assessed by quantitative RNA sequencing data from the Allen Human Brain Atlas resource. VGF (neurosecretory protein VGF) expression was significantly increased during development during the prenatal to childhood through adult stages in the anterior cingulate cortex, dorsolateral prefrontal cortex, inferolateral temporal cortex, orbital frontal cortex, posteroventral parietal cortex, primary somatosensory cortex, and primary visual cortex regions. SCG2 (secretogranin 2) expression was also significantly increased from prenatal to infancy through adult stages in anterior cingulate cortex, dorsolateral prefrontal cortex, inferolateral temporal cortex, orbital frontal cortex, posterior superior temporal cortex, posteroventral parietal cortex, primary somatosensory cortex, and primary visual cortex. A modest number of brain regions showed increased CHGA, CHGB, and SCG3 expression in the postnatal periods compared to the prenatal periods. Further, the SCG5, PCSK1N, and GNAS genes displayed minimal changes throughout development. Overall, these results demonstrate developmental upregulation of VGF and SCG2 genes, with lesser upregulation of CHGA, CHGB, and SCG3 genes, and almost no changes in SCG5, PCSK1N, and GNAS genes during development. These findings illustrate the differential regulation of granin genes during human brain development.

Lipid droplets (LDs), once considered inert lipid stores, are now recognized as active regulators of lipid metabolism, stress responses, and protein quality control in the brain. Their dysregulation is increasingly linked to neurodegenerative diseases, notably Parkinson's disease (PD). This review explores the emerging bidirectional relationship between LDs and α-synuclein (α-Syn), a key pathological hallmark of PD. α-Syn can promote LD accumulation by modulating lipid metabolism and inhibiting lipolysis, while LDs can facilitate α-Syn aggregation through specific lipid-protein and membrane interactions. We summarize current evidence on LD structure, function, and dynamics in neuronal and glial cells, and discuss how alterations in lipid composition, oxidative stress, and associated proteins contribute to PD pathology. Understanding the LD-α-Syn interplay reveals new avenues for therapeutic strategies aimed at restoring lipid homeostasis, enhancing LD turnover, and reducing α-Syn toxicity.