Molecular and Cellular Neuroscience最新文献

{"title":"Endogenous epitope tagging of eEF1A2 in mice reveals early embryonic expression of eEF1A2 and subcellular compartmentalisation of neuronal eEF1A1 and eEF1A2","authors":"Faith C.J. Davies ,&nbsp;Grant F. Marshall ,&nbsp;Eleanor Pegram ,&nbsp;Danni Gadd ,&nbsp;Catherine M. Abbott","doi":"10.1016/j.mcn.2023.103879","DOIUrl":"10.1016/j.mcn.2023.103879","url":null,"abstract":"<div><p>All vertebrate species express two independently-encoded forms of translation elongation factor eEF1A. In humans and mice eEF1A1 and eEF1A2 are 92 % identical at the amino acid level, but the well conserved developmental switch between the two variants in specific tissues suggests the existence of important functional differences. Heterozygous mutations in eEF1A2 result in neurodevelopmental disorders in humans; the mechanism of pathogenicity is unclear, but one hypothesis is that there is a dominant negative effect on eEF1A1 during development. The high degree of similarity between the eEF1A proteins has complicated expression analysis in the past; here we describe a gene edited mouse line in which we have introduced a V5 tag in the gene encoding eEF1A2. Expression analysis using anti-V5 and anti-eEF1A1 antibodies demonstrates that, in contrast to the prevailing view that eEF1A2 is only expressed postnatally, it is expressed from as early as E11.5 in the developing neural tube. Two colour immunofluorescence also reveals coordinated switching between eEF1A1 and eEF1A2 in different regions of postnatal brain. Completely reciprocal expression of the two variants is seen in post-weaning mouse brain with eEF1A1 expressed in oligodendrocytes and astrocytes and eEF1A2 in neuronal soma. Although eEF1A1 is absent from neuronal cell bodies after development, it is widely expressed in axons. This expression does not appear to coincide with myelin sheaths originating from oligodendrocytes but rather results from localised translation within the axon, suggesting that both variants are transcribed in neurons but show completely distinct subcellular localisation at the protein level. These findings will form an underlying framework for understanding how missense mutations in eEF1A2 result in neurodevelopmental disorders.</p></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"126 ","pages":"Article 103879"},"PeriodicalIF":3.5,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10168577","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Expanded polyQ aggregates interact with sarco-endoplasmic reticulum calcium ATPase and Drosophila inhibitor of apoptosis protein1 to regulate polyQ mediated neurodegeneration in Drosophila","authors":"Chandan Kumar Maurya,&nbsp;Madhu G. Tapadia","doi":"10.1016/j.mcn.2023.103886","DOIUrl":"10.1016/j.mcn.2023.103886","url":null,"abstract":"<div><p><span>Polyglutamine (polyQ) induced neurodegeneration<span> is one of the leading causes of progressive neurodegenerative disorders characterized clinically by deteriorating movement defects, psychiatric disability, and dementia. Calcium [Ca</span></span>²⁺<span><span>] homeostasis, which is essential for the functioning of neuronal cells, is disrupted under these pathological conditions. In this paper, we simulated </span>Huntington's disease phenotype in the neuronal cells of the </span><em>Drosophila</em> eye and identified [Ca²⁺<span><span>] pump, sarco-endoplasmic reticulum calcium ATPase (SERCA), as one of the </span>genetic<span> modifiers of the neurodegenerative phenotype. This paper shows genetic and molecular interaction between polyglutamine (polyQ) aggregates, SERCA and DIAP1. We present evidence that polyQ aggregates interact with SERCA and alter its dynamics, resulting in a decrease in cytosolic [Ca</span></span>²⁺] and an increase in ER [Ca²⁺<span>], and thus toxicity. Downregulating SERCA lowers the enhanced calcium levels in the ER and rescues, morphological and functional defects caused due to expanded polyQ repeats. Cell proliferation markers such as Yorkie (Yki), Scalloped (Sd), and phosphatidylinositol 3 kinases/protein kinase B (PI3K/Akt), also respond to varying levels of calcium due to genetic manipulations, adding to the amelioration of degeneration. These results imply that neurodegeneration due to expanded polyQ repeats is sensitive to SERCA activity, and its manipulation can be an important step toward its therapeutic measures.</span></p></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"126 ","pages":"Article 103886"},"PeriodicalIF":3.5,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10223627","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A novel anti-apoptotic role for Cdc42/ACK-1 signaling in neurons","authors":"Noelle C. Punessen ,&nbsp;Claudia Pena ,&nbsp;Alexandra Sandberg ,&nbsp;Lilia A. Koza ,&nbsp;Daniel A. Linseman","doi":"10.1016/j.mcn.2023.103865","DOIUrl":"10.1016/j.mcn.2023.103865","url":null,"abstract":"<div><p>Neurodegenerative diseases such as amyotrophic lateral sclerosis, Alzheimer's and Parkinson's disease are caused by a progressive and aberrant destruction of neurons in the brain and spinal cord. These disorders lack effective long-term treatments that impact the underlying mechanisms of pathogenesis and as a result, existing options focus primarily on alleviating symptomology. Dysregulated programmed cell death (i.e., apoptosis) is a significant contributor to neurodegeneration, and is controlled by a number of different factors. Rho family GTPases are molecular switches with recognized importance in proper neuronal development and migration that have more recently emerged as central regulators of apoptosis and neuronal survival. Here, we investigated a role for the Rho GTPase family member, Cdc42, and its downstream effectors, in neuronal survival and apoptosis. We initially induced apoptosis in primary cultures of rat cerebellar granule neurons (CGNs) by removing both growth factor-containing serum and depolarizing potassium from the cell medium. We then utilized both chemical inhibitors and adenoviral shRNA targeted to Cdc42 to block the function of Cdc42 or its downstream effectors under either control or apoptotic conditions. Our in vitro studies demonstrate that functional inhibition of Cdc42 or its downstream effector, activated Cdc42-associated tyrosine kinase-1 (ACK-1), had no adverse effects on CGN survival under control conditions, but significantly sensitized neurons to cell death under apoptotic conditions. In conclusion, our results suggest a key pro-survival role for Cdc42/ACK-1 signaling in neurons, particularly in regulating neuronal susceptibility to pro-apoptotic stress such as that observed in neurodegenerative disorders.</p></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"126 ","pages":"Article 103865"},"PeriodicalIF":3.5,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10156650","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Glutamine metabolism in diseases associated with mitochondrial dysfunction","authors":"Rebecca Bornstein ,&nbsp;Michael T. Mulholland ,&nbsp;Margaret Sedensky ,&nbsp;Phil Morgan ,&nbsp;Simon C. Johnson","doi":"10.1016/j.mcn.2023.103887","DOIUrl":"10.1016/j.mcn.2023.103887","url":null,"abstract":"<div><p>Mitochondrial dysfunction can arise from genetic defects or environmental exposures and impact a wide range of biological processes. Among these are metabolic pathways involved in glutamine catabolism, anabolism, and glutamine-glutamate cycling. In recent years, altered glutamine metabolism has been found to play important roles in the pathologic consequences of mitochondrial dysfunction. Glutamine is a pleiotropic molecule, not only providing an alternate carbon source to glucose in certain conditions, but also playing unique roles in cellular communication in neurons and astrocytes. Glutamine consumption and catabolic flux can be significantly altered in settings of genetic mitochondrial defects or exposure to mitochondrial toxins, and alterations to glutamine metabolism appears to play a particularly significant role in neurodegenerative diseases. These include primary mitochondrial diseases like Leigh syndrome (subacute necrotizing encephalopathy) and MELAS (mitochondrial myopathy with encephalopathy, lactic acidosis, and stroke-like episodes), as well as complex age-related neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. Pharmacologic interventions targeting glutamine metabolizing and catabolizing pathways appear to provide some benefits in cell and animal models of these diseases, indicating glutamine metabolism may be a clinically relevant target. In this review, we discuss glutamine metabolism, mitochondrial disease, the impact of mitochondrial dysfunction on glutamine metabolic processes, glutamine in neurodegeneration, and candidate targets for therapeutic intervention.</p></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"126 ","pages":"Article 103887"},"PeriodicalIF":3.5,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10164885","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of germ-free status on transcriptional profiles in the nucleus accumbens and transcriptomic response to chronic morphine","authors":"Jonathon P. Sens ,&nbsp;Rebecca S. Hofford ,&nbsp;Drew D. Kiraly","doi":"10.1016/j.mcn.2023.103874","DOIUrl":"10.1016/j.mcn.2023.103874","url":null,"abstract":"<div><p><span><span><span>Opioid use disorder is a public health crisis that causes tremendous suffering for patients as well as substantial social and economic costs for society. There are currently available treatments for patients with opioid use disorder, but they remain intolerable or ineffective for many. Thus the need to develop new avenues for therapeutics development in this space is great. Substantial work in models of substance use disorders, including opioid use disorder, demonstrates that prolonged exposure to drugs of abuse leads to marked transcriptional and epigenetic dysregulation in limbic substructures. It is widely believed that these changes in gene regulation in response to drugs are a key driving factor in the perpetuation of drug taking and seeking </span>behaviors. Thus, development of interventions that could shape transcriptional regulation in response to drugs of abuse would be of high value. Over the past decade there has been a surge in research demonstrating that the resident bacteria of the </span>gastrointestinal tract<span>, collectively the gut microbiome, can have tremendous influence on neurobiological and behavioral plasticity. Previous work from our group and others has demonstrated that alterations in the gut microbiome can alter behavioral responses to opioids in multiple paradigms. Additionally, we have previously reported that depletion of the gut microbiome with antibiotics markedly shifts the </span></span>transcriptome<span> of the nucleus accumbens<span> following prolonged morphine exposure. In this manuscript we present a comprehensive analysis of the effects of the gut microbiome on transcriptional regulation of the nucleus accumbens following morphine by utilizing germ-free, antibiotic treated, and control mice. This allows for detailed understanding of the role of the microbiome in regulating baseline transcriptomic control, as well as response to morphine. We find that germ-free status leads to a marked gene dysregulation in a manner distinct to adult mice treated with antibiotics, and that altered gene pathways are highly related to cellular metabolic processes. These data provide additional insight into the role of the gut microbiome in modulating brain function and lay a foundation for further study in this area.</span></span></p></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"126 ","pages":"Article 103874"},"PeriodicalIF":3.5,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10166564","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Profiling transcriptomic responses of human stem cell-derived medium spiny neuron-like cells to exogenous phasic and tonic neurotransmitters","authors":"Ryan W Tam PhD,&nbsp;Albert J. Keung","doi":"10.1016/j.mcn.2023.103876","DOIUrl":"10.1016/j.mcn.2023.103876","url":null,"abstract":"<div><p><span><span><span>Transcriptomic<span> responses to neurotransmitters contribute to the complex processes driving memory and addiction. Advances in both measurement methods and experimental models continue to improve our understanding of this regulatory layer. Here we focus on the experimental potential of stem cell derived neurons, currently the only ethical model that can be used in reductionist and experimentally perturbable studies of human cells. Prior work has focused on generating distinct cell types from human stem cells, and has also shown their utility in modeling development and cellular phenotypes related to </span></span>neurodegeneration<span>. Here we seek an understanding of how stem cell derived neural cultures respond to perturbations experienced during development and disease progression. This work profiles transcriptomic responses of human medium spiny neuron-like cells with three specific goals. We first characterize transcriptomic responses to dopamine and dopamine receptor agonists and antagonists presented in dosing patterns mimicking acute, chronic, and withdrawal regimens. We also assess transcriptomic responses to low and persistent tonic levels of dopamine, </span></span>acetylcholine, and </span>glutamate to better mimic the in vivo environment. Finally, we identify similar and distinct responses between hMSN-like cells derived from H9 and H1 stem cell lines, providing some context for the extent of variability these types of systems will likely pose for experimentalists. The results here suggest future optimizations of human stem cell derived neurons to increase their in vivo relevance and the biological insights that can be garnered from these models.</p></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"126 ","pages":"Article 103876"},"PeriodicalIF":3.5,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10528483/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10157127","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Recovery of motor function is associated with rescue of glutamate biomarkers in the striatum and motor cortex following treatment with Mucuna pruriens in a murine model of Parkinsons disease","authors":"Tanya Denne ,&nbsp;Lila C. Winfrey ,&nbsp;Cindy Moore ,&nbsp;Chase Whitner ,&nbsp;Theresa D'Silva ,&nbsp;Amala Soumyanath ,&nbsp;Lynne Shinto ,&nbsp;Amie Hiller ,&nbsp;Charles K. Meshul","doi":"10.1016/j.mcn.2023.103883","DOIUrl":"10.1016/j.mcn.2023.103883","url":null,"abstract":"<div><p><span>There is growing interest in the use of natural products for the treatment of Parkinson's disease (PD). </span><span><em>Mucuna</em><em> pruriens</em></span><span> has been used in the treatment of humans with PD. The goal of this study was to determine if daily oral treatment with an extract of </span><em>Mucuna pruriens</em><span><span><span>, starting after the MPTP-induced loss of nigrostriatal dopamine in male mice, would result in recovery/restoration of motor function, tyrosine hydroxylase<span> (TH) protein expression in the </span></span>nigrostriatal pathway, or </span>glutamate<span><span> biomarkers in both the striatum and motor cortex. Following </span>MPTP administration, resulting in an 80 % loss of striatal TH, treatment with </span></span><em>Mucuna pruriens</em><span> failed to rescue either striatal TH or the dopamine transporter<span> back to the control levels, but there was restoration of gait/motor function. There was an MPTP-induced loss of TH-labeled neurons in the substantia nigra pars compacta<span> and in the number of striatal dendritic spines, both of which failed to be recovered following treatment with </span></span></span><em>Mucuna pruriens</em>. This <em>Mucuna pruriens</em><span>-induced locomotor recovery following MPTP was associated with restoration of two striatal glutamate transporter proteins<span><span>, GLAST (EAAT1) and EAAC1 (EAAT3), and the </span>vesicular glutamate transporter 2 (Vglut2) within the motor cortex. Post-MPTP treatment with </span></span><em>Mucuna pruriens</em>, results in locomotor improvement that is associated with recovery of striatal and motor cortex glutamate transporters but is independent of nigrostriatal TH restoration.</p></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"126 ","pages":"Article 103883"},"PeriodicalIF":3.5,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10166333","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Satellite glial cell-secreted exosomes after in-vitro oxaliplatin treatment presents a pro-nociceptive effect for dorsal root ganglion neurons and induce mechanical hypersensitivity in naïve mice","authors":"Liping Zhao ,&nbsp;Shijiang Liu ,&nbsp;Xiaobao Zhang ,&nbsp;Juan Yang ,&nbsp;Mao Mao ,&nbsp;Susu Zhang ,&nbsp;Shiqin Xu ,&nbsp;Shanwu Feng ,&nbsp;Xian Wang","doi":"10.1016/j.mcn.2023.103881","DOIUrl":"10.1016/j.mcn.2023.103881","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background&lt;/h3&gt;&lt;p&gt;&lt;span&gt;&lt;span&gt;The pathophysiological mechanism underlying chemotherapy-induced neuropathic pain (CINP) remains unclear. Sensory neuronal hypersensitivity in the &lt;/span&gt;dorsal root ganglion&lt;span&gt; (DRG) is essential for the onset and maintenance of chronic pain. Satellite glial cells (SGCs) in the DRG potentially affect the function of &lt;/span&gt;&lt;/span&gt;sensory neurons&lt;span&gt;, possibly by mediating extracellular or paracrine signaling. Exosomes play an essential role in cell-cell communication. However, the role of SGC-secreted exosomes in glia-neuron communication and CINP remains unclear.&lt;/span&gt;&lt;/p&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;p&gt;&lt;span&gt;&lt;span&gt;&lt;span&gt;SGCs and sensory neurons were cultured from the DRG of mice. The SGCs were treated with 4 μM oxaliplatin for 24 h. Glial fibrillary &lt;/span&gt;acid protein&lt;span&gt;&lt;span&gt; (GFAP) and connexin-43 (Cx-43) expressions in the SGCs were examined with immunocytochemistry (ICC). Enzyme-linked immunosorbent assay (ELISA) detected &lt;/span&gt;cytokine release in the SGCs after oxaliplatin treatment. Subsequently, SGC-secreted exosomes were collected using &lt;/span&gt;&lt;/span&gt;ultracentrifugation&lt;span&gt; and identified by nanoparticle tracking analysis, transmission electron microscopy&lt;span&gt;&lt;span&gt;&lt;span&gt;, and western blotting. Subsequently, DRG neurons were incubated with SGC-secreted exosomes for 24 h. The percentage of &lt;/span&gt;reactive oxygen species (ROS)-positive neurons was detected using flow cytometry, and acid-sensing ion channel 3 (ASIC3) and &lt;/span&gt;transient receptor potential vanilloid 1 (TRPV1) expression were examined by western blotting. SGC-secreted exosomes were intrathecally injected into naïve mice. The mechanical withdrawal threshold was assessed 24, 48, and 72 h following the injection. TRPV1 expression in the DRG was examined 72 h after &lt;/span&gt;&lt;/span&gt;&lt;/span&gt;intrathecal&lt;span&gt;&lt;span&gt; injection. Furthermore, differentially expressed (DE) miRNAs within the SGC-secreted exosomes were detected using &lt;/span&gt;RNA sequencing&lt;span&gt; and bioinformatics analysis. Gene Ontology (GO) enrichment, Kyoto Encyclopedia of Genes and Genomes (KEGG), and Reactome pathway analyses were performed to predict the function of the target genes of DE miRNAs. Finally, the DE miRNAs with pain regulation potential were identified in silico.&lt;/span&gt;&lt;/span&gt;&lt;/p&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;p&gt;&lt;span&gt;&lt;span&gt;After in-vitro oxaliplatin treatment, ICC showed an increase in the immunoreactivity of GFAP and Cx-43 in the SGCs. ELISA results suggested an increased release of tumor necrosis factor-α and &lt;/span&gt;interleukin (IL)-1β, but a decreased release of IL-10. Oxaliplatin treatment increased the secretion of exosomes in the SGCs from 4.34 to 5.99 × 10&lt;/span&gt;&lt;sup&gt;11&lt;/sup&gt;&lt;span&gt; (particles/ml). The exosome-specific markers CD9&lt;span&gt;&lt;span&gt; and TSG101&lt;span&gt;&lt;span&gt; were positive, whereas calnexin was negative for the obtained exosomes. Additionally, the SGC-secreted exosomes were endocytosed by DRG neurons after co-incubation. Moreover, after incubati","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"126 ","pages":"Article 103881"},"PeriodicalIF":3.5,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10167107","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Npc2Gt(LST105)BygNya mouse signifies pathological changes comparable to human Niemann-Pick type C2 disease","authors":"Charlotte Laurfelt Munch Rasmussen ,&nbsp;Louiza Bohn Thomsen ,&nbsp;Christian Würtz Heegaard ,&nbsp;Torben Moos ,&nbsp;Annette Burkhart","doi":"10.1016/j.mcn.2023.103880","DOIUrl":"https://doi.org/10.1016/j.mcn.2023.103880","url":null,"abstract":"<div><h3>Introduction</h3><p><span>Niemann-Pick type C2 disease (NP-C2) is a fatal neurovisceral disorder caused by defects in the lysosomal cholesterol transporter protein NPC2. Consequently, cholesterol and other lipids accumulate within the </span>lysosomes, causing a heterogeneous spectrum of clinical manifestations. Murine models are essential for increasing the understanding of the complex pathology of NP-C2. This study, therefore, aims to describe the neurovisceral pathology in the NPC2-deficient mouse model to evaluate its correlation to human NP-C2.</p></div><div><h3>Methods</h3><p><em>Npc2</em>−/− mice holding the LST105 mutation were used in the present study (<em>Npc2</em>^{<em>Gt(LST105)BygNya</em>}). Body and organ weight and histopathological evaluations were carried out in six and 12-week-old <em>Npc2</em><span><span>−/− mice, with a special emphasis on neuropathology. The Purkinje cell<span> (PC) marker calbindin, the astrocytic marker </span></span>GFAP<span><span>, and the microglia<span> marker IBA1 were included to assess PC degeneration and neuroinflammation, respectively. In addition, the pathology of the liver, lungs, and spleen was assessed using </span></span>hematoxylin<span><span> and eosin </span>staining.</span></span></span></p></div><div><h3>Results</h3><p>Six weeks old pre-symptomatic <em>Npc2</em><span>−/− mice showed splenomegaly and obvious neuropathological changes, especially in the cerebellum, where initial PC loss and neuroinflammation were evident. The </span><em>Npc2</em>−/− mice developed neurological symptoms at eight weeks of age, severely progressing until the end-stage of the disease at 12 weeks. At the end-stage of the disease, <em>Npc2</em><span>−/− mice were characterized by growth retardation, tremor, cerebellar ataxia, splenomegaly, foam cell accumulation in the lungs, liver, and spleen, brain atrophy, pronounced PC degeneration, and severe neuroinflammation.</span></p></div><div><h3>Conclusion</h3><p>The <em>Npc2</em>^{<em>Gt(LST105)BygNya</em>} mouse model resembles the pathology seen in NP-C2 patients and denotes a valuable model for increasing the understanding of the complex disease manifestation and is relevant for testing the efficacies of new treatment strategies.</p></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"126 ","pages":"Article 103880"},"PeriodicalIF":3.5,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49858578","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The molecular neural mechanism underlying the acceleration of brain aging due to Dcf1 deficiency","authors":"Haicong Zhou ,&nbsp;Jiao Wang ,&nbsp;Tieqiao Wen","doi":"10.1016/j.mcn.2023.103884","DOIUrl":"10.1016/j.mcn.2023.103884","url":null,"abstract":"<div><p><span>Owing to the continuous increase in human life expectancy, the management of aging-related diseases has become an urgent issue. The brain dominates the central nervous system<span>; therefore, brain aging is a key area of aging-related research. We previously uncovered that dendritic cell factor 1 (</span></span><em>Dcf1</em><span>) maintains the stemness of neural stem cells and its expression in </span><em>Drosophila</em> can prolong lifespan, suggesting an association between <em>Dcf1</em><span> and aging; however, the specific underlying neural mechanism remains unclear. In the present study, we show for the first time that hippocampal neurogenesis is decreased in aged </span><em>Dcf1</em>^−/− mice, which leads to a decrease in the number of brain neurons and an increased number of senescent cells. Moreover, astrocytes proliferate abnormally and express elevated mRNA levels of aging-related factors, in addition to displaying increased activation of Akt and Foxo3a. Finally, behavioral tests confirm that aged <em>Dcf1</em>^−/− mice exhibit a significant decline in cognitive abilities related to learning and memory. In conclusion, we reveal a novel mechanism underlying brain aging triggered by <em>Dcf1</em> deficiency at the molecular, cellular, tissue, and behavioral levels, providing a new perspective for the exploration of brain aging.</p></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"126 ","pages":"Article 103884"},"PeriodicalIF":3.5,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10166324","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}