Cellular and Molecular Neurobiology最新文献

Central nervous system diseases include central nervous system injury diseases, neurodegenerative diseases, and other conditions. MicroRNAs (miRNAs) are important regulators of gene expression, with therapeutic potential in modulating genes, pathways, and cells associated with central nervous system injury diseases. This article comprehensively reviews the therapeutic role of exosomal miRNAs in various central nervous system injury diseases, including traumatic brain injury, ischemic stroke, intracerebral hemorrhage, optic nerve injury, and spinal cord injury. This review covers the pathophysiology, animal models, miRNA transfection, administration methods, behavioral tests for evaluating treatment efficacy, and the mechanisms of action of miRNA-based therapies. Finally, this article discusses the future directions of miRNA therapy for central nervous system injury diseases.

The neuroendocrine-immune (NEI) network is fundamental for maintaining body's homeostasis and health. While the roles of microRNAs (miRNAs) and transcription factors (TFs) in disease processes are well-established, their synergistic regulation within the NEI network has yet to be elucidated. In this study, we constructed a background NEI-related miRNA-TF regulatory network (NEI-miRTF-N) by integrating NEI signaling molecules (including miRNAs, genes, and TFs) and identifying miRNA-TF feed-forward loops. Our analysis reveals that the number of immune signaling molecules is the highest and suggests potential directions for signal transduction, primarily from the nervous system to both the endocrine and immune systems, as well as from the endocrine system to the immune system. Furthermore, disease-specific NEI-miRTF-Ns for depression, Alzheimer's disease (AD) and dilated cardiomyopathy (DCM) were constructed based on the known disease molecules and significantly differentially expressed (SDE) molecules. Additionally, we proposed a novel method using depth-first-search algorithm for identifying significantly dysregulated NEI-related miRNA-TF regulatory pathways (NEI-miRTF-Ps) and verified their reliability from multiple perspectives. Our study provides an effective approach for identifying disease-specific NEI-miRTF-Ps and offers new insights into the synergistic regulation of miRNAs and TFs within the NEI network. Our findings provide information for new therapeutic strategies targeting these regulatory pathways.

Transmembrane member 16A (TMEM16A) exhibits a negative correlation with autophagy, though the underlying mechanism remains elusive. This study investigates the mechanism between TMEM16A and autophagy by inducing autophagy in DRG neuronal cells using Rapamycin. Results indicated that TMEM16A interference augmented cell viability and reduced Rapamycin-induced apoptosis. Autophagosome formation increased with TMEM16A interference but decreased upon overexpression. A similar increase in autophagosomes was observed with SB203580 treatment. Furthermore, TMEM16A interference suppressed Rapamycin-induced gene and protein expression of p38 MAPK and mTOR, whereas overexpression had the opposite effect. These findings suggest that TMEM16A activation inhibits autophagy in DRG cells, which is associated with the p38 MAPK/mTOR pathway, offering a potential target for mitigating neuropathic pain (NP).

Microscopic, membranous vesicles known as extracellular vesicles (EVs) have been proposed to play a role in the mechanisms underlying central nervous system (CNS) diseases. EVs are secreted by a variety of cells, including myeloid, endothelial, microglial, oligodendroglial, and mesenchymal stem cells (MSCs). Body fluids such as plasma, urine, and cerebrospinal fluid (CSF) contain microparticles (MPs). The detection of MPs in CSF may indicate genetic or environmental susceptibility to conditions such as schizophrenia, schizoaffective disorder, and bipolar disorder. MPs of different origins can exhibit changes in specific biomarkers at various stages of the disease, aiding in the diagnosis and monitoring of neurological conditions. However, understanding the role and clinical applications of MPs is complicated by challenges such as their isolation and dual roles within the CNS. In this review, we discuss the history, characteristics, and roles of MPs in CNS diseases. We also provide practical insights for future research and highlight the challenges that obscure the therapeutic potential of MPs.

Alzheimer's disease (AD) is a condition characterized by the gradual degeneration of the nervous system that poses significant challenges to cognitive function and overall mental health. Given the increasing global life expectancy, there is an urgent need for effective strategies to prevent and manage Alzheimer's disease, with a particular focus on anti-aging interventions. Recent scientific advancements have unveiled several promising strategies for combating Alzheimer's disease (AD), ranging from lifestyle interventions to cutting-edge pharmacological treatments and therapies targeting the underlying biological processes of aging and AD. Regular physical exercise, cognitive engagement, a balanced diet, and social interaction serve as key pillars in maintaining brain health. At the same time, therapies target key pathological mechanisms of AD, such as amyloid-beta accumulation, tau abnormalities, neuroinflammation, mitochondrial dysfunction, and synaptic loss, offering potential breakthroughs in treatment. Moreover, cutting-edge innovations such as gene therapy, stem cell transplantation, and novel drug delivery systems are emerging as potential game-changers in the fight against AD. This review critically evaluates the latest research on anti-aging interventions and their potential in preventing and treating Alzheimer's disease (AD) by exploring the connections between aging mechanisms and AD pathogenesis. It provides a comprehensive analysis of both well-established and emerging strategies, while also identifying key gaps in current knowledge to guide future research efforts.

Regional neuropathic pain syndromes above, at, or below the site of spinal damage arise after spinal cord injury (SCI) and are believed to entail distinct pathways; nevertheless, they may share shared defective glial systems. Neuropathic pain after SCI is caused by glial cells, ectopic firing of neurons endings and their intra- and extracellular signaling mechanisms. One such mechanism occurs when stimuli that were previously non-noxious become so after the injury. This will exhibit a symptom of allodynia. Another mechanism is the release of substances by glia, which keeps the sensitivity of dorsal horn neurons even in regions distant from the site of injury. Here, we review, the models and identifications of SCI-induced neuropathic pain (SCI-NP), the mechanisms of SCI-NP related to glia, and the treatments of SCI-NP.

Photobiomodulation (PBM) is a safe and effective neurotherapy that modulates cellular pathways by altering cell membrane potentials, leading to beneficial biological effects such as anti-inflammatory and neuroregenerative responses. This review compiles studies from PubMed up to March 2024, investigating the impact of light at wavelengths ranging from 620 to 1270 nm on ion channels. Out of 330 articles screened, 19 met the inclusion criteria. Research indicates that PBM can directly affect various ion channels by influencing neurotransmitter synthesis in neighboring cells, impacting receptors like glutamate and acetylcholine, as well as potassium, sodium channels, and transient receptor potential channels. The diversity of studies hampers a comprehensive meta-analysis for evaluating treatment strategies effectively. This systematic review aims to explore the potential role of optoelectronic signal transduction in PBM, studying the neurobiological mechanisms and therapeutic significance of PBM on ion channels. However, the lack of uniformity in current treatment methods underscores the necessity of establishing standardized and reliable therapeutic approaches.

Reactive astrogliosis and inflammation are pathologic hallmarks of spinal cord injury. After injury, dysfunction of glial cells (astrocytes) results in glial scar formation, which limits neuronal regeneration. The blood-spinal cord barrier maintains the structural and functional integrity of the spinal cord and does not allow blood vessel components to leak into the spinal cord microenvironment. After the injury, disruption in the spinal cord barrier causes an imbalance of the immunological microenvironment. This triggers the process of neuroinflammation, facilitated by the actions of microglia, neutrophils, glial cells, and cytokines production. Recent work has revealed two phenotypes of astrocytes, A1 and A2, where A2 has a protective type, and A1 releases neurotoxins, further promoting glial scar formation. Here, we first describe the current understanding of the spinal cord microenvironment, both pre-, and post-injury, and the role of different glial cells in the context of spinal cord injury, which forms the essential update on the cellular and molecular events following injury. We aim to explore in-depth signaling pathways and molecular mediators that trigger astrocyte activation and glial scar formation. This review will discuss the activated signaling pathways in astrocytes and other glial cells and their collaborative role in the development of gliosis through inflammatory responses.

Rasopathies are genetic disorders often associated with developmental delay and intellectual disability. Noonan syndrome (NS) is one of the most common Rasopathies, caused by mutations in PTPN11 in more than 50% of cases. In mammalian neurons, PTPN11 controls the trafficking of postsynaptic glutamate receptors. This process is disrupted in neurons expressing PTPN11 variants associated with Rasopathies and is thought to contribute to the cognitive impairments in Noonan syndrome. Recent work revealed presynaptic impairments upon expression of RASopathy-linked PTPN11 variants in Drosophila. However, the presynaptic role of PTPN11 has not yet been addressed in mammals. Here, we investigated membrane trafficking of synaptic vesicles in cultured mouse cortical neurons expressing Rasopathy-associated PTPN11^D61Y variant. We observed a significantly smaller readily releasable and total recycling pool of synaptic vesicles. The drop in synaptic vesicle release competence was accompanied by a decreased rate of SV retrieval. Interestingly, the presynaptic phenotype was evident in mature (DIV21) but not in immature (DIV12) neurons. Thus, our data reveal importance of balanced PTPN11 activity for normal trafficking of neurotransmitter-filled synaptic vesicles in the presynaptic ending of mature neurons.

Wnt signaling plays a role in synaptic plasticity, but the specific cellular events and molecular components involved in Wnt signaling-mediated synaptic plasticity are not well defined. Here, we report a change in the threshold required to induce synaptic plasticity that facilitates the induction of long-term potentiation (LTP) and inhibits the induction of long-term depression (LTD) during brief exposure to the noncanonical ligand Wnt-5a. Both effects are related to the metaplastic switch of hippocampal CA3-CA1 synaptic transmission, a complex mechanism underlying the regulation of the threshold required to induce synaptic plasticity and of synaptic efficacy. We observed an early increase in the amplitude of field excitatory postsynaptic potentials (fEPSPs) that persisted over time, including after washout. The first phase involves an increase in the fEPSP amplitude that is required to trigger a spontaneous second phase that depends on Jun N-terminal kinase (JNK) and N-methyl D-aspartate receptor (NMDAR) activity. These changes are prevented by treatment with secreted frizzled-related protein 2 (sFRP-2), an endogenous antagonist of Wnt ligands. Here, we demonstrate the contribution of Wnt-5a signaling to a process associated with metaplasticity at CA3-CA1 synapses that favors LTP over LTD.