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Genes To Cells : Devoted To Molecular &... Aug 2023Methotrexate (MTX) is an anti-metabolite that has been used for the treatment of patients of acute lymphocytic leukemia or non-Hodgikin lymphoma for decades. In some...
Methotrexate (MTX) is an anti-metabolite that has been used for the treatment of patients of acute lymphocytic leukemia or non-Hodgikin lymphoma for decades. In some cases, MTX-treated patients suffer from neurological side effects, including seizures and cognitive dysfunctions. While most patients are at developmental stages, information of the mechanisms of the side effects of MTX treatment on the developing neurons has been limited. Neurons develop in five steps in the human brain: neurogenesis, polarity formation, dendrite and axon development, synapse formation, and neuronal death. Except for neurogenesis, these processes can be recapitulated in the primary culture system of cortical neurons. Using primary cultured cortical neurons, we studied the impact of MTX treatment on dendrite development, synapse formation, and neuronal death in the present report. MTX treatment impaired neuronal survival, dendrite development, and synapse formation. Interestingly, half maximal effective concentrations (EC s) of MTX for all three processes are at the similar range and lower than the MTX concentration in the cerebrospinal fluid in treated patients. Our results provide possible mechanisms of neurological side effects in treated patients.
Topics: Humans; Methotrexate; Neurons; Neurogenesis; Dendrites; Synapses
PubMed: 37170756
DOI: 10.1111/gtc.13035 -
Scientific Reports Jan 2024Ectodermal neural cortex 1 (ENC1) is a protein that plays a crucial role in the regulation of various cellular processes such as cell proliferation, differentiation, and... (Review)
Review
Ectodermal neural cortex 1 (ENC1) is a protein that plays a crucial role in the regulation of various cellular processes such as cell proliferation, differentiation, and apoptosis. Numerous studies have shown that ENC1 is overexpressed in various types of cancers, including breast, lung, pancreatic, and colorectal cancer, and its upregulation is correlated with a poorer prognosis. In addition to its role in cancer growth and spreading, ENC1 has also been linked to neuronal process development and neural crest cell differentiation. In this review, we provide an overview of the current knowledge on the relationship between ENC1 and cancer. We discuss the molecular mechanisms by which ENC1 contributes to tumorigenesis, including its involvement in multiple oncogenic signaling pathways. We also summarize the potential of targeting ENC1 for cancer therapy, as its inhibition has been shown to significantly reduce cancer cell invasion, growth, and metastasis. Finally, we highlight the remaining gaps in our understanding of ENC1's role in cancer and propose potential directions for future research.
Topics: Microfilament Proteins; Neoplasms; Neurites; Nuclear Proteins; Humans
PubMed: 38177640
DOI: 10.1038/s41598-023-50914-7 -
Cell Reports May 2024Neuronal morphology influences synaptic connectivity and neuronal signal processing. However, it remains unclear how neuronal shape affects steady-state distributions of...
Neuronal morphology influences synaptic connectivity and neuronal signal processing. However, it remains unclear how neuronal shape affects steady-state distributions of organelles like mitochondria. In this work, we investigated the link between mitochondrial transport and dendrite branching patterns by combining mathematical modeling with in vivo measurements of dendrite architecture, mitochondrial motility, and mitochondrial localization patterns in Drosophila HS (horizontal system) neurons. In our model, different forms of morphological and transport scaling rules-which set the relative thicknesses of parent and daughter branches at each junction in the dendritic arbor and link mitochondrial motility to branch thickness-predict dramatically different global mitochondrial localization patterns. We show that HS dendrites obey the specific subset of scaling rules that, in our model, lead to realistic mitochondrial distributions. Moreover, we demonstrate that neuronal activity does not affect mitochondrial transport or localization, indicating that steady-state mitochondrial distributions are hard-wired by the architecture of the neuron.
Topics: Animals; Dendrites; Mitochondria; Drosophila melanogaster; Drosophila; Neurons
PubMed: 38717903
DOI: 10.1016/j.celrep.2024.114190 -
Progress in Neuro-psychopharmacology &... Feb 2024Severe mental illnesses (SMI) collectively affect approximately 20% of the global population, as estimated by the World Health Organization (WHO). Despite having diverse... (Review)
Review
Severe mental illnesses (SMI) collectively affect approximately 20% of the global population, as estimated by the World Health Organization (WHO). Despite having diverse etiologies, clinical symptoms, and pharmacotherapies, these diseases share a common pathophysiological characteristic: the misconnection of brain areas involved in reality perception, executive control, and cognition, including the corticolimbic system. Dendritic spines play a crucial role in excitatory neurotransmission within the central nervous system. These small structures exhibit remarkable plasticity, regulated by factors such as neurotransmitter tone, neurotrophic factors, and innate immunity-related molecules, and other mechanisms - all of which are associated with the pathophysiology of SMI. However, studying dendritic spine mechanisms in both healthy and pathological conditions in patients is fraught with technical limitations. This is where animal models related to these diseases become indispensable. They have played a pivotal role in elucidating the significance of dendritic spines in SMI. In this review, the information regarding the potential role of dendritic spines in SMI was summarized, drawing from clinical and animal model reports. Also, the implications of targeting dendritic spine-related molecules for SMI treatment were explored. Specifically, our focus is on major depressive disorder and the neurodevelopmental disorders schizophrenia and autism spectrum disorder. Abundant clinical and basic research has studied the functional and structural plasticity of dendritic spines in these diseases, along with potential pharmacological targets that modulate the dynamics of these structures. These targets may be associated with the clinical efficacy of the pharmacotherapy.
Topics: Animals; Humans; Dendritic Spines; Autism Spectrum Disorder; Depressive Disorder, Major; Brain; Synaptic Transmission; Neuronal Plasticity; Synapses
PubMed: 37863171
DOI: 10.1016/j.pnpbp.2023.110876 -
Cell Reports Mar 2024Stroke, trauma, and neurodegenerative disorders cause loss of neurites (axons and dendrites) in addition to neuronal death. Neurite loss may result directly from a...
Stroke, trauma, and neurodegenerative disorders cause loss of neurites (axons and dendrites) in addition to neuronal death. Neurite loss may result directly from a primary insult, secondary to parental neuron death, or secondary to a post-injury inflammatory response. Here, we use lipopolysaccharide and the alarmin S100β to selectively evaluate neurite loss caused by the inflammatory response. Activation of microglia and infiltrating macrophages by these stimuli causes neurite loss that far exceeds neuronal death, both in vitro and in vivo. Neurite loss is accompanied by the formation of cofilactin rods and aggregates (CARs), which are polymers of cofilin-1 and actin induced by oxidative stress and other factors. Mice deficient in either cofilin-1 or the superoxide-generating enzyme NADPH oxidase-2 show reduced CAR formation, neurite loss, and motor impairment. The findings identify a mechanism by which inflammation leads to neurite loss via CAR formation and highlight the relevance of neurite loss to functional impairment.
Topics: Mice; Animals; Neurites; Neurons; Axons; Neurodegenerative Diseases; Inflammation
PubMed: 38451813
DOI: 10.1016/j.celrep.2024.113914 -
Neuron Jul 2023Dendritic spine remodeling in the dorsal horn is associated with many chronic pain models. Li et al. demonstrate that Tiam1 links Rac1-mediated spine changes to NMDA...
Dendritic spine remodeling in the dorsal horn is associated with many chronic pain models. Li et al. demonstrate that Tiam1 links Rac1-mediated spine changes to NMDA receptor activity to promote behavioral signs of chronic pain in rodents.
Topics: Humans; Receptors, N-Methyl-D-Aspartate; Chronic Pain; Dendritic Spines; Signal Transduction; Neurons; rac1 GTP-Binding Protein
PubMed: 37413965
DOI: 10.1016/j.neuron.2023.06.001 -
Cells Sep 2023While astrocyte-to-neuron (AtN) reprogramming holds great promise in regenerative medicine, the molecular mechanisms that govern this unique biological process remain...
While astrocyte-to-neuron (AtN) reprogramming holds great promise in regenerative medicine, the molecular mechanisms that govern this unique biological process remain elusive. To understand the function of miRNAs during the AtN reprogramming process, we performed RNA-seq of both mRNAs and miRNAs on human astrocyte (HA) cultures upon NeuroD1 overexpression. Bioinformatics analyses showed that NeuroD1 not only activated essential neuronal genes to initiate the reprogramming process but also induced miRNA changes in HA. Among the upregulated miRNAs, we identified miR-375 and its targets, neuronal ELAVL genes (nELAVLs), which encode a family of RNA-binding proteins and were also upregulated by NeuroD1. We further showed that manipulating the miR-375 level regulated nELAVLs' expression during NeuroD1-mediated reprogramming. Interestingly, miR-375/nELAVLs were also induced by the reprogramming factors Neurog2 and ASCL1 in HA, suggesting a conserved function to neuronal reprogramming, and by NeuroD1 in the mouse astrocyte culture and spinal cord. Functionally, we showed that miR-375 overexpression improved NeuroD1-mediated reprogramming efficiency by promoting cell survival at early stages in HA and did not appear to compromise the maturation of the reprogrammed neurons. Lastly, overexpression of miR-375-refractory ELAVL4 induced apoptosis and reversed the cell survival-promoting effect of miR-375 during AtN reprogramming. Together, we demonstrated a neuroprotective role of miR-375 during NeuroD1-mediated AtN reprogramming.
Topics: Humans; Animals; Mice; Astrocytes; Neurons; Neurites; Apoptosis; MicroRNAs; Nerve Tissue Proteins; Basic Helix-Loop-Helix Transcription Factors
PubMed: 37681934
DOI: 10.3390/cells12172202 -
The Journal of Physiology Aug 2023Neuron models with explicit dendritic dynamics have shed light on mechanisms for coincidence detection, pathway selection and temporal filtering. However, it is still...
Neuron models with explicit dendritic dynamics have shed light on mechanisms for coincidence detection, pathway selection and temporal filtering. However, it is still unclear which morphological and physiological features are required to capture these phenomena. In this work, we introduce the Tripod neuron model and propose a minimal structural reduction of the dendritic tree that is able to reproduce these computations. The Tripod is a three-compartment model consisting of two segregated passive dendrites and a somatic compartment modelled as an adaptive, exponential integrate-and-fire neuron. It incorporates dendritic geometry, membrane physiology and receptor dynamics as measured in human pyramidal cells. We characterize the response of the Tripod to glutamatergic and GABAergic inputs and identify parameters that support supra-linear integration, coincidence-detection and pathway-specific gating through shunting inhibition. Following NMDA spikes, the Tripod neuron generates plateau potentials whose duration depends on the dendritic length and the strength of synaptic input. When fitted with distal compartments, the Tripod encodes previous activity into a dendritic depolarized state. This dendritic memory allows the neuron to perform temporal binding, and we show that it solves transition and sequence detection tasks on which a single-compartment model fails. Thus, the Tripod can account for dendritic computations previously explained only with more detailed neuron models or neural networks. Due to its simplicity, the Tripod neuron can be used efficiently in simulations of larger cortical circuits. KEY POINTS: We present a neuron model, called the Tripod, with two segregated dendritic branches that are connected to an axosomatic compartment. Each branch implements inhibitory GABAergic and excitatory glutamatergic synaptic transmission, including voltage-gated NMDA receptors. Dendrites are modelled on relevant geometric and physiological parameters measured in human pyramidal cells. The neuron reproduces classical dendritic computations, such as coincidence detection and pathway selection via shunting inhibition, that are beyond the scope of point-neuron models. Under some conditions, dendritic NMDA spikes cause plateau potentials, and we show that they provide a form of short-term memory which is useful for sequence recognition. The dendritic structure of the Tripod neuron is sufficiently simple to be integrated into efficient network simulations and studied in a broad functional context.
Topics: Humans; Dendrites; N-Methylaspartate; Synapses; Models, Neurological; Neurons; Pyramidal Cells; Action Potentials
PubMed: 36168736
DOI: 10.1113/JP283399 -
BMC Medicine Jul 2023Schizophrenia and bipolar disorder (BD) are believed to share clinical symptoms, genetic risk, etiological factors, and pathogenic mechanisms. We previously reported...
BACKGROUND
Schizophrenia and bipolar disorder (BD) are believed to share clinical symptoms, genetic risk, etiological factors, and pathogenic mechanisms. We previously reported that single nucleotide polymorphisms spanning chromosome 3p21.1 showed significant associations with both schizophrenia and BD, and a risk SNP rs2251219 was in linkage disequilibrium with a human specific Alu polymorphism rs71052682, which showed enhancer effects on transcriptional activities using luciferase reporter assays in U251 and U87MG cells.
METHODS
CRISPR/Cas9-directed genome editing, real-time quantitative PCR, and public Hi-C data were utilized to investigate the correlation between the Alu polymorphism rs71052682 and NISCH. Primary neuronal culture, immunofluorescence staining, co-immunoprecipitation, lentiviral vector production, intracranial stereotaxic injection, behavioral assessment, and drug treatment were used to examine the physiological impacts of Nischarin (encoded by NISCH).
RESULTS
Deleting the Alu sequence in U251 and U87MG cells reduced mRNA expression of NISCH, the gene locates 180 kb from rs71052682, and Hi-C data in brain tissues confirmed the extensive chromatin contacts. These data suggested that the genetic risk of schizophrenia and BD predicted elevated NISCH expression, which was also consistent with the observed higher NISCH mRNA levels in the brain tissues from psychiatric patients compared with controls. We then found that overexpression of NISCH resulted in a significantly decreased density of mushroom dendritic spines with a simultaneously increased density of thin dendritic spines in primary cultured neurons. Intriguingly, elevated expression of this gene in mice also led to impaired spatial working memory in the Y-maze. Given that Nischarin is the target of anti-hypertensive agents clonidine and tizanidine, which have shown therapeutic effects in patients with schizophrenia and patients with BD in preliminary clinical trials, we demonstrated that treatment with those antihypertensive drugs could reduce NISCH mRNA expression and rescue the impaired working memory in mice.
CONCLUSIONS
We identify a psychiatric risk gene NISCH at 3p21.1 GWAS locus influencing dendritic spine morphogenesis and cognitive function, and Nischarin may have potentials for future therapeutic development.
Topics: Humans; Mice; Animals; Dendritic Spines; Genome-Wide Association Study; Cognition; Polymorphism, Single Nucleotide; Morphogenesis; RNA, Messenger
PubMed: 37443018
DOI: 10.1186/s12916-023-02931-6 -
Neurobiology of Aging Feb 2024We assessed white matter (WM) integrity in MAPT mutation carriers (16 asymptomatic, 5 symptomatic) compared to 31 non-carrier family controls using diffusion tensor...
We assessed white matter (WM) integrity in MAPT mutation carriers (16 asymptomatic, 5 symptomatic) compared to 31 non-carrier family controls using diffusion tensor imaging (DTI) (fractional anisotropy; FA, mean diffusivity; MD) and neurite orientation dispersion and density imaging (NODDI) (neurite density index; NDI, orientation and dispersion index; ODI). Linear mixed-effects models accounting for age and family relatedness revealed alterations across DTI and NODDI metrics in all mutation carriers and in symptomatic carriers, with the most significant differences involving fronto-temporal WM tracts. Asymptomatic carriers showed higher entorhinal MD and lower cingulum FA and patterns of higher ODI mostly involving temporal areas and long association and projections fibers. Regression models between estimated time to or time from disease and DTI and NODDI metrics in key regions (amygdala, cingulum, entorhinal, inferior temporal, uncinate fasciculus) in all carriers showed increasing abnormalities with estimated time to or time from disease onset, with FA and NDI showing the strongest relationships. Neurite-based metrics, particularly ODI, appear to be particularly sensitive to early WM involvement in asymptomatic carriers.
Topics: Brain; Diffusion Magnetic Resonance Imaging; Diffusion Tensor Imaging; Mutation; Neurites; White Matter; Humans; Heterozygote; tau Proteins
PubMed: 38091751
DOI: 10.1016/j.neurobiolaging.2023.12.001