Molecular and Cellular Neuroscience最新文献

{"title":"The exocyst subunit Sec15 is critical for proper synaptic development and function at the Drosophila NMJ","authors":"Chris J. Kang ,&nbsp;Luis E. Guzmán-Clavel ,&nbsp;Katherine Lei ,&nbsp;Martin Koo ,&nbsp;Steven To ,&nbsp;John P. Roche","doi":"10.1016/j.mcn.2023.103914","DOIUrl":"10.1016/j.mcn.2023.103914","url":null,"abstract":"<div><p>The exocyst protein complex is important for targeted vesicle fusion in a variety of cell types, however, its function in neurons is still not entirely known. We found that presynaptic knockdown (KD) of the exocyst component <em>sec15</em> by transgenic RNAi expression caused a number of unexpected morphological and physiological defects in the synapse. These include the development of active zones (AZ) devoid of essential presynaptic proteins, an increase in the branching of the presynaptic arbor, the appearance of satellite boutons, and a decrease in the amplitude of stimulated postsynaptic currents as well as a decrease in the frequency of spontaneous synaptic vesicle release. We also found the release of extracellular vesicles from the presynaptic neuron was greatly diminished in the Sec15 KDs. These effects were mimicked by presynaptic knockdown of Rab11, a protein known to interact with the exocyst. <em>sec15 RNAi</em> expression caused an increase in phosphorylated Mothers against decapentaplegic (pMad) in the presynaptic terminal, an indication of enhanced bone morphogenic protein (BMP) signaling. Some morphological phenotypes caused by Sec15 knockdown were reduced by attenuation of BMP signaling through knockdown of <em>wishful thinking (Wit</em>), while other phenotypes were unaffected. Individual knockdown of multiple proteins of the exocyst complex also displayed a morphological phenotype similar to Sec15 KD. We conclude that Sec15, functioning as part of the exocyst complex, is critically important for proper formation and function of neuronal synapses. We propose a model in which Sec15 is involved in the trafficking of vesicles from the recycling endosome to the cell membrane as well as possibly trafficking extracellular vesicles for presynaptic release and these processes are necessary for the correct structure and function of the synapse.</p></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"128 ","pages":"Article 103914"},"PeriodicalIF":3.5,"publicationDate":"2023-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1044743123001082/pdfft?md5=44dcb81f68b5b0609f5ada63093ea1ac&pid=1-s2.0-S1044743123001082-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138584388","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":"Suppression of BMP signaling restores mitral cell development impaired by FGF signaling deficits in mouse olfactory bulb","authors":"Ayako Ito,&nbsp;Claire Miller,&nbsp;Fumiaki Imamura","doi":"10.1016/j.mcn.2023.103913","DOIUrl":"10.1016/j.mcn.2023.103913","url":null,"abstract":"<div><p><span>Fibroblast growth factors (FGFs) and </span>bone morphogenic proteins<span><span><span> (BMPs) play various important roles in the development of the central nervous system<span><span>. However, the roles of FGF and BMP signaling in the development of the olfactory bulb<span> (OB) are largely unknown. In this study, we first showed the expression of FGF receptors (FGFRs) and BMP receptors (BMPRs) in OB </span></span>RGCs, radial glial cells (RGCs) in the developing OB, which generate the OB projection neurons, mitral and </span></span>tufted cells<span>. When the FGF signaling was inhibited by a dominant-negative form of FGFR1 (dnFGFR1), OB RGCs accelerated their state transition to mitral cell precursors without affecting their transcription cascade and fate. However, the mitral cell precursors could not radially migrate to form the mitral cell layer (MCL). In addition, FGF signaling inhibition reduced the expression of a BMP antagonist, </span></span>Noggin<span>, in the developing OB. When BMP signaling was suppressed by the ectopic expression of Noggin or a dominant-negative form of BMPR1a (dnBMPR1a) in the developing OB, the defect in MCL formation caused by the dnFGFR1 was rescued. However, the dnBMPR1a did not rescue the accelerated state transition of OB RGCs. These results demonstrate that FGF signaling is important for OB RGCs to maintain their self-renewal state and MCL formation. Moreover, the suppression of BMP signaling is required for mitral cells to form the MCL. This study sheds new light on the roles of FGFs and BMPs in OB development.</span></span></p></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"128 ","pages":"Article 103913"},"PeriodicalIF":3.5,"publicationDate":"2023-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138498862","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":"Neuron navigators: A novel frontier with physiological and pathological implications","authors":"Parth Sandeep ,&nbsp;Poonam Sharma ,&nbsp;Kanishk Luhach ,&nbsp;Neerupma Dhiman ,&nbsp;Harsha Kharkwal ,&nbsp;Bhupesh Sharma","doi":"10.1016/j.mcn.2023.103905","DOIUrl":"10.1016/j.mcn.2023.103905","url":null,"abstract":"<div><p><span>Neuron navigators are microtubule plus-end tracking proteins containing basic and serine rich regions which are encoded by neuron navigator genes (</span><em>NAVs</em><span><span>). Neuron navigator proteins are essential for neurite outgrowth<span><span><span>, neuronal migration, and overall </span>neurodevelopment<span> along with some other functions as well. The navigator proteins are substantially expressed in the developing brain and have been reported to be differentially expressed in various tissues at different ages. Over the years, the research has found neuron navigators to be implicated in a spectrum of pathological conditions such as developmental anomalies, neurodegenerative disorders, </span></span>neuropathic pain, anxiety, cancers, and certain inflammatory conditions. The existing knowledge about neuron navigators remains sparse owing to their differential functions, undiscovered modulators, and unknown molecular mechanisms. Investigating the possible role of neuron navigators in various </span></span>physiological processes and pathological conditions pose as a novel field that requires extensive research and might provide novel mechanistic insights and understanding of these aspects.</span></p></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"127 ","pages":"Article 103905"},"PeriodicalIF":3.5,"publicationDate":"2023-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135764530","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 elastin-derived peptide (VGVAPG) activates autophagy in neuroblastoma (SH-SY5Y) cells via peroxisome proliferator-activated receptor gamma (PPARγ)","authors":"Konrad A. Szychowski,&nbsp;Bartosz Skóra","doi":"10.1016/j.mcn.2023.103902","DOIUrl":"10.1016/j.mcn.2023.103902","url":null,"abstract":"<div><p>Autophagy is a self-degradative process important for balancing the sources of energy and involved in the development of Alzheimer's disease (AD). To date, a number of papers have shown that elastin-derived peptides (EDPs) affect the expression and activation of peroxisome proliferator-activated receptor gamma (PPARγ), which is crucial for the development of AD and autophagy initiation. Therefore, the aim of the present study was to determine whether EDPs with a Val–Gly–Val–Ala–Pro–Gly (VGVAPG) amino acid sequence activate the autophagic process in undifferentiated SH-SY5Y human neuroblastoma cells. Our study is the first to show that EDPs with the VGVAPG sequence initiate the autophagy process in the undifferentiated SH-SY5Y cell line exhibiting a number of features of normal neuroblasts. In particular, we observed in our study that VGAVPG peptide increased ULK1, AKT, PPARγ, and LC3B protein expression. Moreover, our experiments with the agonist (rosiglitazone) and antagonist (GW9662) of PPARγ confirm that the studied EDP acts through the PPARγ pathway affecting mTOR and finally autophagy. Some studies have shown that autophagy disturbances are involved in the development of AD. Therefore, we believe that our study will provide new evidence of the possible involvement of EDPs (especially VGVAPG) in the development of AD.</p></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"127 ","pages":"Article 103902"},"PeriodicalIF":3.5,"publicationDate":"2023-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1044743123000969/pdfft?md5=fa4c7ef43c6fc1a0439ce02b36a326ca&pid=1-s2.0-S1044743123000969-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71425065","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":"Alpha-secretase dependent nuclear localization of the amyloid-β precursor protein-binding protein Fe65 promotes DNA repair","authors":"Rebecca S. Revol,&nbsp;Niina A. Koistinen,&nbsp;Preeti K. Menon,&nbsp;Almudena Chicote-Gonzàlez,&nbsp;Kerstin Iverfeldt ,&nbsp;Anna-Lena Ström","doi":"10.1016/j.mcn.2023.103903","DOIUrl":"10.1016/j.mcn.2023.103903","url":null,"abstract":"<div><p>Fe65 is a brain enriched adaptor protein involved in various cellular processes, including actin cytoskeleton regulation, DNA repair and transcription. A well-studied interacting partner of Fe65 is the transmembrane amyloid-β precursor protein (APP), which can undergo regulated intramembrane proteolysis (RIP). Following β- and γ-secretase-mediated RIP, the released APP intracellular domain (AICD) together with Fe65 can translocate to the nucleus and regulate transcription. In this study, we investigated if Fe65 nuclear localization can also be regulated by different α-secretases, also known to participate in RIP of APP and other transmembrane proteins. We found that in both Phorbol 12-myristate 13-acetate and all-trans retinoic acid differentiated neuroblastoma cells a strong negative impact on Fe65 nuclear localization, equal to the effect observed upon γ-secretase inhibition, could be detected following inhibition of all three (ADAM9, ADAM10 and ADAM17) α-secretases. Moreover, using the comet assay and analysis of Fe65 dependent DNA repair associated posttranslational modifications of histones, we could show that inhibition of α-secretase-mediated Fe65 nuclear translocation resulted in impaired capacity of the cells to repair DNA damage. Taken together this suggests that α-secretase processing of APP and/or other Fe65 interacting transmembrane proteins play an important role in regulating Fe65 nuclear translocation and DNA repair.</p></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"127 ","pages":"Article 103903"},"PeriodicalIF":3.5,"publicationDate":"2023-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1044743123000970/pdfft?md5=86f63fd27ceb1975c8da32015ef75c5f&pid=1-s2.0-S1044743123000970-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71424954","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":"Role of ALS-associated OPTN-K489E mutation in neuronal cell-death regulation","authors":"Dibyakanti Mishra ,&nbsp;Priyam Narain ,&nbsp;Upma Dave ,&nbsp;James Gomes","doi":"10.1016/j.mcn.2023.103904","DOIUrl":"10.1016/j.mcn.2023.103904","url":null,"abstract":"<div><p>Optineurin (<em>OPTN)</em> gene is a marker of amyotrophic lateral sclerosis (ALS). However, the role of optineurin protein (OPTN) in ALS pathology is unclear, even though it is known to regulate autophagy, apoptosis, and other survival-death cellular processes. Genetic analysis of Indian ALS patients by our group ascertained a novel mutation K489E in the <em>OPTN</em> gene. To identify the molecular mechanism associated with OPTN and its mutation, we developed an in-vitro cell model using SH-SY5Y cells harbouring OPTN and OPTN-K489E mutation along with its control vector. Since we observed a significant decrease in cell viability in the mutant, we measured the expressions of genes and proteins mediating apoptosis, necroptosis, and autophagy, to establish the role of OPTN in cell death regulation. Our results show that OPTN-K489E mutation changes the relative gene expressions of miRNA-9, REST, CoREST and BDNF, and causes apoptosis. We also observed an up-regulation in the expressions of necroptosis mediated genes RIPK1, RIPK3, and MLKL and autophagy mediated genes TBK1, P62, and LC3II. The results of FACS analyses revealed that this mutation promotes apoptotic and necroptotic processes confirming the pathogenicity of OPTN-K489E.</p></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"127 ","pages":"Article 103904"},"PeriodicalIF":3.5,"publicationDate":"2023-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71424955","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 NIDA Avenir award in genetics or epigenetics of substance use disorders","authors":"John S. Satterlee ,&nbsp;Jonathan D. Pollock ,&nbsp;Nora D. Volkow","doi":"10.1016/j.mcn.2023.103899","DOIUrl":"10.1016/j.mcn.2023.103899","url":null,"abstract":"<div><p>NIDA's Avenir Program in the Genetics<span> or Epigenetics of Substance Use Disorders (SUDs) was launched to support early stage investigators who propose innovative, high risk, but potentially high impact research and who show promise of being tomorrow's leaders in this scientific field. Since 2015, NIDA has supported 30 Avenir Investigators with unique expertise and creative ideas. This special issue showcases how some of these ideas have germinated, flourished, and borne fruit. In this perspective article we briefly describe the purpose and implementation of the Avenir award and provide a high altitude overview of the awardees and their scientific projects to date.</span></p></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"127 ","pages":"Article 103899"},"PeriodicalIF":3.5,"publicationDate":"2023-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41134748","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 intrinsic apoptotic pathway lies upstream of reactive species production in cortical neurons and age-related oxidative stress in the brain","authors":"Kyndra Stovall ,&nbsp;Mital Patel ,&nbsp;James L. Franklin","doi":"10.1016/j.mcn.2023.103901","DOIUrl":"10.1016/j.mcn.2023.103901","url":null,"abstract":"<div><p><span><span>A BAX- and mitochondria-dependent production of reactive oxygen species (ROS) and reactive species (reactive nitrogen species, RNS) lying downstream of these ROS occurs in apoptotic and nonapoptotic mouse sympathetic neurons and cerebellar </span>granule cells<span> in cell culture. These ROS have been shown to lie downstream of caspase 3<span><span> in mouse sympathetic neurons. Here we show that BAX is necessary for similar ROS production in apoptotic and nonapoptotic mouse cortical neurons in cell culture and that it also positively regulates oxidative stress<span><span> in the brains of mice of different ages. Brains from mice with genetically reduced levels of mitochondrial superoxide dismutase 2 (SOD2) exhibited elevated levels of </span>DNA strand breaks consistent with oxidative damage. </span></span>Lipid peroxides<span> were also elevated at some ages in comparison to the brains of wild type animals. BAX deletion in these mice reduced both brain DNA strand breaks and lipid peroxide levels to well below those of wild type animals. Deletion of caspase 3 greatly reduced age-augmented levels of brain oxidative stress markers including lipid peroxides, oxidized DNA, and nitrosylated proteins. These findings indicate that BAX contributes to ROS production in mouse cortical neurons, to oxidative stress their brains, and that this effect is likely mediated </span></span></span></span><em>via</em> caspase 3 activity.</p></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"127 ","pages":"Article 103901"},"PeriodicalIF":3.5,"publicationDate":"2023-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41104817","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":"Efferent axons in the zebrafish lateral line degenerate following sensory hair cell ablation","authors":"Melek Umay Tuz-Sasik,&nbsp;Remy Manuel,&nbsp;Henrik Boije","doi":"10.1016/j.mcn.2023.103900","DOIUrl":"10.1016/j.mcn.2023.103900","url":null,"abstract":"<div><p>The zebrafish lateral line is a frequently used model to study the mechanisms behind peripheral neuronal innervation of sensory organs and the regeneration thereof. The lateral line system consists of neuromasts, a cluster of protruding hair cells, which are innervated by sensory afferent and modulatory efferent neurons. These flow-sensing hair cells are similar to the hair cells in the mammalian ear. Though, while hair cell loss in humans is irreversible, the zebrafish neuromasts are regarded as the fastest regenerating structure in vertebrates, making them an ideal model to study regeneration. However, one component of the lateral line system, the efferent projections, has largely been omitted in regenerative studies. Here, for the first time, we bring insights into the fate of efferent axons during ablation and regeneration of the hair cells in the zebrafish lateral line. Our behavioral analysis showed functional recovery of hair cells and sensory transmission within 48 h and their regeneration were in line with previous studies. Analysis of the inhibitory efferent projections revealed that in approximately half the cases the inhibitory efferent axons degenerated, which was never observed for the sensory afferent axons. Quantification of hair cells following ablation suggests that the presence of mature hair cells in the neuromast may prevent axon degeneration. Within 120 h, degenerated efferent axons regenerated along the axonal tract of the lateral line. Reanalysis of published single cell neuromast data hinted to a role for Bdnf in the survival of efferent axons. However, sequestering Bdnf, blocking the Trk-receptors, and inhibiting the downstream ERK-signaling, did not induce axon degeneration, indicating that efferent survival is not mediated through neurotrophic factors. To further explore the relation between hair cells and efferent projections, we generated <em>atoh1a</em> mutants, where mature hair cells never form. In larvae lacking hair cells, inhibitory efferent projections were still present, following the tract of the sensory afferent without displaying any innervation. Our study reveal the fate of efferent innervation following hair cell ablation and provide insights into the inherent differences in regeneration between neurons in the peripheral and central nervous system.</p></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"127 ","pages":"Article 103900"},"PeriodicalIF":3.5,"publicationDate":"2023-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10288761","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":"Proglucagon signalling in the rat Dorsomedial Hypothalamus – Physiology and high-fat diet-mediated alterations","authors":"A.M. Sanetra ,&nbsp;K. Palus-Chramiec ,&nbsp;L. Chrobok ,&nbsp;J.S. Jeczmien-Lazur ,&nbsp;J.D. Klich ,&nbsp;M.H. Lewandowski","doi":"10.1016/j.mcn.2023.103873","DOIUrl":"10.1016/j.mcn.2023.103873","url":null,"abstract":"<div><p>A relatively new pharmacological target in obesity treatment has been the preproglucagon (PPG) signalling, predominantly with glucagon-like peptide (GLP) 1 receptor agonists. As far as the PPG role within the digestive system is well recognised, its actions in the brain remain understudied. Here, we investigated PPG signalling in the Dorsomedial Hypothalamus (DMH), a structure involved in feeding regulation and metabolism, using in situ hybridisation, electrophysiology, and immunohistochemistry. Our experiments were performed on animals fed both control, and high-fat diet (HFD), uncovering HFD-mediated alterations. First, sensitivity to exendin-4 (Exn4, a GLP1R agonist) was shown to increase under HFD, with a higher number of responsive neurons. The amplitude of the response to both Exn4 and oxyntomodulin (Oxm) was also altered, diminishing its relationship with the cells' spontaneous firing rate. Not only neuronal sensitivity, but also GLP1 presence, and therefore possibly release, was influenced by HFD. Immunofluorescent labelling of the GLP1 showed changes in its density depending on the metabolic state (fasted/fed), but this effect was eliminated by HFD feeding. Interestingly, these dietary differences were absent after a period of restricted feeding, allowing for an anticipation of the alternating metabolic states, which suggests possible prevention of such outcome.</p></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"126 ","pages":"Article 103873"},"PeriodicalIF":3.5,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10166554","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}