Journal of Neurochemistry最新文献

{"title":"Prenatal Alcohol Consumption Alters Protein Fingerprint in Umbilical Cord Blood Serum and Induces Brain Microvascular Endothelial Cell Dysfunction","authors":"Paula Silva Lacerda Almeida,&nbsp;Dayana Araújo,&nbsp;Juliana Minardi Nascimento,&nbsp;Alex C. Manhães,&nbsp;Nilson Ramires Jesus,&nbsp;Joice Stipursky","doi":"10.1111/jnc.70015","DOIUrl":"https://doi.org/10.1111/jnc.70015","url":null,"abstract":"<div>\u0000 \u0000 <p>Consumption of alcoholic beverages during pregnancy is directly related to the establishment of fetal alcohol spectrum disorders (FASD), which includes craniofacial changes, body growth restriction, and neurodevelopment impairments. Proper functioning of the central nervous system (CNS) depends on blood–brain barrier (BBB) development, which is formed by interactions of vascular endothelial cells, pericytes, astrocytes, and basal lamina. Gestational exposure to ethanol has been demonstrated to impair CNS development; however, little is known about ethanol modulation of blood circulating factors and impacts on human developing BBB. Here we investigated the prevalence of alcohol consumption during pregnancy and found that 27% of pregnant women reported alcohol consumption, mainly in the first trimester. Control and alcohol-exposed newborns showed no differences in weight, length, and appearance, pulse, grimace, activity, respiration (APGAR) score at birth. In vitro, we cultivated human brain microcapillary endothelial cells (HBMEC) and treated with umbilical cord blood serum (UCBS) from control (S-Control) newborns or ethanol-exposed ones (S-Ethanol). S-Ethanol treatment induced 68% and 38% decreases in protein levels of ZO-1 (tight junction) and GLUT-1 (glucose transporter type-1), respectively, increased endothelial monolayer permeability, migratory potential impairment, and changes in angiogenesis-related secreted proteins profile, compared to S-Control treatments. UCBS proteomics revealed a total of 392 proteins, 10 exclusively found in S-Ethanol, mostly related to innate and adaptive immunity and tissue injury response. These results suggest that gestational exposure to ethanol contributes to blood altered protein profiles triggering BBB endothelial.\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>\u0000 </div>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 2","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143362466","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":"Transcript and Lipid Profile Alterations in Astrocyte-Neuron Mitochondrial Transfer Under Lipopolysaccharide Exposure: An In Vitro Study","authors":"Yufei Kan,&nbsp;Hong Wang,&nbsp;Huaying Lin,&nbsp;Yongfa Li,&nbsp;Shuaijie Pei,&nbsp;Yan Cui,&nbsp;Keliang Xie,&nbsp;Hongguang Chen,&nbsp;Yonghao Yu","doi":"10.1111/jnc.70003","DOIUrl":"https://doi.org/10.1111/jnc.70003","url":null,"abstract":"<p>Sepsis-associated encephalopathy (SAE) is a brain dysfunction for which no effective therapy currently exists. Recent studies suggest that transferring mitochondria from astrocytes to neurons may benefit SAE patients, though the underlying mechanism remains unclear. We cultured astrocytes and neurons from mice in vitro. Astrocytes were stimulated with lipopolysaccharide (LPS) for 24 h, and the astrocyte-conditioned medium (ACM) was collected. Neuronal cultures were then treated with ACM or mitochondria-depleted ACM (mdACM) for further analysis. Mitochondrial transfer was examined under a fluorescence microscope. Western blotting analyzed the protein expression of genes related to apoptosis and mitochondrial metabolism. RNA sequencing and mass spectrometry were employed to investigate the mechanisms underlying mitochondrial transfer. Astrocyte-derived mitochondria migrated toward and connected with LPS-exposed neurons. The addition of ACM significantly attenuated LPS-induced alterations in the proteins linked to apoptosis and mitochondrial dynamics. RNA sequencing revealed notable alterations in the transcript profile of neurons upon ACM treatment, highlighting the involvement of mitochondria metabolism, inflammation, and apoptosis-related factors. Additionally, mitochondrial transfer modified the lipid composition of neurons, increasing phosphatidylserine levels, which correlated with neuroinflammation and enriched pathways related to cytokine and MAPK signaling. Our findings suggest that astrocyte-neuron mitochondrial transfer holds therapeutic potential for alleviating SAE, possibly through the anti-inflammatory effects of lipids, particularly phosphatidylserine.\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 2","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.70003","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143112161","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":"Focused Ultrasound Modulates Dopamine in a Mesolimbic Reward Circuit","authors":"Greatness Olaitan,&nbsp;Mallikarjunarao Ganesana,&nbsp;Andrew Strohman,&nbsp;Wendy J. Lynch,&nbsp;Wynn Legon,&nbsp;B. Jill Venton","doi":"10.1111/jnc.70001","DOIUrl":"https://doi.org/10.1111/jnc.70001","url":null,"abstract":"<p>Dopamine is a neurotransmitter that plays a significant role in reward and motivation. Dysfunction in the mesolimbic dopamine pathway has been linked to a variety of psychiatric disorders, including addiction. Low-intensity focused ultrasound (LIFU) has demonstrated effects on brain activity, but how LIFU affects dopamine neurotransmission is not known. Here, we applied three different intensities (6.5, 13, and 26 W/cm² <i>I</i>_SPPA) of 2-min LIFU to the prelimbic cortex (PLC) and measured dopamine in the nucleus accumbens (NAc) core using fast-scan cyclic voltammetry. Two minutes of LIFU sonication at 13 W/cm² to the PLC significantly reduced dopamine release by ~50% for up to 2 h. However, double the intensity (26 W/cm²) resulted in less inhibition (~30%), and half the intensity (6.5 W/cm²) did not result in any inhibition of dopamine. Anatomical controls applying LIFU to the primary somatosensory cortex did not change NAc core dopamine, and applying LIFU to the PLC did not affect dopamine release in the caudate or NAc shell. Histological evaluations showed no evidence of cell damage or death. Modeling temperature rise demonstrates a maximum temperature change of 0.5°C with 13 W/cm², suggesting that modulation is not due to thermal mechanisms. These studies show that LIFU at a moderate intensity provides a noninvasive, high spatial resolution means to modulate specific mesolimbic circuits that could be used in future studies to target and repair pathways that are dysfunctional in addiction and other psychiatric diseases.\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 2","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.70001","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143112162","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":"FOXP1 is a Transcription Factor for the Alzheimer's Disease Risk Gene SORL1","authors":"Xiaofeng Fu,&nbsp;Shuiyue Quan,&nbsp;Wenping Liang,&nbsp;Yu Li,&nbsp;Huimin Cai,&nbsp;Ziye Ren,&nbsp;Yinghao Xu,&nbsp;Zhe Wang,&nbsp;Longfei Jia","doi":"10.1111/jnc.70011","DOIUrl":"https://doi.org/10.1111/jnc.70011","url":null,"abstract":"<div>\u0000 \u0000 <p>Sortilin-related receptor 1 (<i>SORL1</i>) is a risk gene of Alzheimer's disease (AD), and some protein-truncating (PTV) and rare missense variants causing the loss of function of SORL1 contribute to AD pathogenesis. SORL1 is an endosomal receptor that interacts with multiple protein sorting complexes to facilitate the transport of various cargoes through the endolysosomal network (ELN). However, the regulatory mechanisms governing <i>SORL1</i> expression remain unknown. Through biochemical methods, we identified Forkhead Box P1 (FOXP1) as a binding protein to the minimal promoter region of <i>SORL1</i> gene. Silencing <i>FOXP1</i> using siRNA significantly decreased the activity of the <i>SORL1</i> minimal promoter and reduced SORL1 protein and mRNA levels in the neuroblastoma cell line SH-SY5Y. Additionally, using 5xFAD mouse models of AD, we observed significantly decreased FOXP1 and SORL1 expression in neurons within the prefrontal cortex. Disruption of ELN and the autophagy degradation system by bafilomycin A1 (BafA1) appeared to be a specific condition to suppress FOXP1 and hence SORL1 in SH-SY5Y cells. These findings highlight the critical role of <i>FOXP1</i> in regulating <i>SORL1</i> expression and suggest that <i>FOXP1</i> could be a potential target to maintain <i>SORL1</i> expression for AD prevention and therapy.\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure>\u0000 </p>\u0000 </div>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 2","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143112160","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":"Challenges and Opportunities in Exploring Non-Motor Symptoms in 6-Hydroxydopamine Models of Parkinson's Disease: A Systematic Review","authors":"Mateus Prates-Rodrigues,&nbsp;Beatriz Lage Araújo Schweizer,&nbsp;Clara de Paula Gomes,&nbsp;Ângela Maria Ribeiro,&nbsp;Fernando E. Padovan-Neto,&nbsp;Debora Masini,&nbsp;Cleiton Lopes-Aguiar","doi":"10.1111/jnc.70008","DOIUrl":"https://doi.org/10.1111/jnc.70008","url":null,"abstract":"<p>Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive loss of midbrain dopaminergic neurons, leading to motor symptoms such as tremors, rigidity, and bradykinesia. Non-motor symptoms, including depression, hyposmia, and sleep disturbances, often emerge in the early stages of PD, but their mechanisms remain poorly understood. The 6-hydroxydopamine (6-OHDA) rodent model is a well-established tool for preclinical research, replicating key motor and non-motor symptoms of PD. In this review, we systematically analyzed 135 studies that used 6-OHDA rodent models of PD to investigate non-motor symptoms. The review process adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Our analysis highlights the growing use of 6-OHDA PD models for experimental research of non-motor symptoms. It also reveals significant variability in methodologies, including choices of brain target, toxin dosage, lesion verification strategies, and behavioral assessment reporting. Factors that hinder reproducibility and comparability of findings across studies. We highlight the need for standardization in 6-OHDA-based models with particular emphasis on consistent evaluation of lesion extent and reporting of the co-occurrence of non-motor symptoms. By fostering methodological coherence, this framework aims to enhance the reproducibility, reliability, and translational value of 6-OHDA models in PD non-motor symptom research.\u0000\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure>\u0000 </p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 2","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.70008","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143111349","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":"Emerging Roles for MFG-E8 in Synapse Elimination","authors":"Marisa G. Aviani,&nbsp;Fred Menard","doi":"10.1111/jnc.70009","DOIUrl":"10.1111/jnc.70009","url":null,"abstract":"<p>Synapse elimination is an essential process in the healthy nervous system and is dysregulated in many neuropathologies. Yet, the underlying molecular mechanisms and under what conditions they occur remain unclear. MFG-E8 is a secreted glycoprotein well known to act as an opsonin, tagging stressed and dying cells for engulfment by phagocytes. Opsonization of cells and debris by MFG-E8 for microglial phagocytosis in the CNS is well established, and its role in astrocytic phagocytosis, and trogocytosis-like engulfment of synapses is beginning to be explored. However, MFG-E8's function in other tissues is highly diverse, and evidence suggests that its role in the nervous system and on synapse elimination in particular may be more complex and varied than opsonization. In this review, we outline the documented direct and indirect effects of MFG-E8 on synapse elimination, while also proposing potential roles to be explored further, in particular, cytoskeletal reorganization of neurites and glia leading to synapse elimination by various mechanisms. Finally, we demonstrate the need for several open questions to be answered—chiefly, under what conditions might MFG-E8-mediated synapse elimination occur in favor of other mechanisms, and when might its activity be dysregulated, increasing unwanted synapse elimination and neurotoxicity?\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 2","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.70009","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074874","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":"Prion Protein Endoproteolysis: Cleavage Sites, Mechanisms and Connections to Prion Disease","authors":"Andrew R. Castle,&nbsp;David Westaway","doi":"10.1111/jnc.16310","DOIUrl":"10.1111/jnc.16310","url":null,"abstract":"<p>Highly abundant in neurons, the cellular prion protein (PrP^C) is an obligatory precursor to the disease-associated misfolded isoform denoted PrP^Sc that accumulates in the rare neurodegenerative disorders referred to either as transmissible spongiform encephalopathies (TSEs) or as prion diseases. The ability of PrP^C to serve as a substrate for this template-mediated conversion process depends on several criteria but importantly includes the presence or absence of certain endoproteolytic events performed at the cell surface or in acidic endolysosomal compartments. The major endoproteolytic events affecting PrP^C are referred to as α- and β-cleavages, and in this review we outline the sites within PrP^C at which the cleavages occur, the mechanisms potentially responsible and their relevance to pathology. Although the association of α-cleavage with neuroprotection is well-supported, we identify open questions regarding the importance of β-cleavage in TSEs and suggest experimental approaches that could provide clarification. We also combine findings from in vitro cleavage assays and mass spectrometry-based studies of prion protein fragments in the brain to present an updated view in which α- and β-cleavages may represent two distinct clusters of proteolytic events that occur at multiple neighbouring sites rather than at single positions. Furthermore, we highlight the candidate proteolytic mechanisms best supported by the literature; currently, despite several proteases identified as capable of processing PrP^C in vitro, in cell-based models and in some cases, in vivo, none have been shown conclusively to cleave PrP^C in the brain. Addressing this knowledge gap will be crucial for developing therapeutic interventions to drive PrP^C endoproteolysis in a neuroprotective direction. Finally, we end this review by briefly addressing other cleavage events, specifically ectodomain shedding, γ-cleavage, the generation of atypical pathological fragments in the familial prion disorder Gerstmann–Sträussler–Scheinker syndrome and the possibility of an additional form of endoproteolysis close to the PrP^C N-terminus.\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11774512/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143059346","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":"GABAB Receptor Modulation of Membrane Excitability in Human Pluripotent Stem Cell-Derived Sensory Neurons by Baclofen and α-Conotoxin Vc1.1","authors":"Mitchell St Clair-Glover,&nbsp;Arsalan Yousuf,&nbsp;Dominic Kaul,&nbsp;Mirella Dottori,&nbsp;David J. Adams","doi":"10.1111/jnc.70004","DOIUrl":"10.1111/jnc.70004","url":null,"abstract":"<p>GABA_B receptor (GABA_BR) activation is known to alleviate pain by reducing neuronal excitability, primarily through inhibition of high voltage-activated (HVA) calcium (Ca_V2.2) channels and potentiating G protein–coupled inwardly rectifying potassium (GIRK) channels. Although the analgesic properties of small molecules and peptides have been primarily tested on isolated murine dorsal root ganglion (DRG) neurons, emerging strategies to develop, study, and characterise human pluripotent stem cell (hPSC)-derived sensory neurons present a promising alternative. In this study, hPSCs were efficiently differentiated into peripheral DRG-induced sensory neurons (iSNs) using a combined chemical and transcription factor-driven approach via a neural crest cell intermediate. Molecular characterisation and transcriptomic analysis confirmed the expression of key DRG markers such as BRN3A, ISLET1, and PRPH, in addition to GABA_BR and ion channels including Ca_V2.2 and GIRK1 in iSNs. Functional characterisation of GABA_BR was conducted using whole-cell patch clamp electrophysiology, assessing neuronal excitability under current-clamp conditions in the absence and presence of GABA_BR agonists baclofen and α-conotoxin Vc1.1. Both baclofen (100 μM) and Vc1.1 (1 μM) significantly reduced membrane excitability by hyperpolarising the resting membrane potential and increasing the rheobase for action potential firing. In voltage-clamp mode, baclofen and Vc1.1 inhibited HVA Ca²⁺ channel currents, which were attenuated by the selective GABA_BR antagonist CGP 55845. However, modulation of GIRK channels by GABA_BRs was not observed in the presence of baclofen or Vc1.1, suggesting that functional GIRK1/2 channels were not coupled to GABA_BRs in hPSC-derived iSNs. This study is the first to report GABA_BR modulation of membrane excitability in iSNs by baclofen and Vc1.1, highlighting their potential as a future model for studying analgesic compounds.\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11773314/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143052819","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":"Interactions of Oligodendrocyte Precursor Cells and Dopaminergic Neurons in the Mouse Substantia Nigra","authors":"Julia C. Fitzgerald,&nbsp;Ying Sun,&nbsp;Frederek Reinecke,&nbsp;Elisabeth Bauer,&nbsp;Olga Garaschuk,&nbsp;Philipp J. Kahle,&nbsp;Friederike Pfeiffer","doi":"10.1111/jnc.16298","DOIUrl":"10.1111/jnc.16298","url":null,"abstract":"<p>Parkinson's disease (PD) is a prevalent neurodegenerative disease caused by the death of dopaminergic neurons within the <i>substantia nigra pars compacta</i> (SNpc) region of the midbrain. Recent genomic and single cell sequencing data identified oligodendrocytes and oligodendrocyte precursor cells (OPCs) to confer genetic risk in PD, but their biological role is unknown. Although SNpc dopaminergic neurons are scarcely or thinly myelinated, there is a gap in the knowledge concerning the physiological interactions between dopaminergic neurons and oligodendroglia. We sought to investigate the distribution of OPCs with regard to the myelination state in the mouse <i>substantia nigra</i> (SN) by high-resolution imaging to provide a morphological assessment of OPC-dopaminergic neuron interactions and quantification of cell numbers across different age groups. OPCs are evenly distributed in the midbrain throughout the lifespan and they physically interact with both the soma and axons of dopaminergic neurons. The presence of OPCs and their interaction with dopaminergic neurons does not correlate with the distribution of myelin. Myelination is sparse in the SNpc, including dopaminergic fibers originating from the SNpc and projecting through the <i>substantia nigra pars reticulata</i> (SNpr). We report that OPCs and dopaminergic neurons exist in a 1:1 ratio in the SNpc, with OPCs accounting for 15%–16% of all cells in the region across all age groups. This description of OPC-dopaminergic neuron interaction in the midbrain provides a first look at their longitudinal distribution in mice, suggesting additional functions of OPCs beyond their differentiation into myelinating oligodendrocytes.\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11773302/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143052822","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":"TRIM9 Controls Growth Cone Responses to Netrin Through DCC and UNC5C","authors":"Sampada P. Mutalik,&nbsp;Chris T. Ho,&nbsp;Ellen C. O'Shaughnessy,&nbsp;Anca G. Frasineanu,&nbsp;Aneri B. Shah,&nbsp;Stephanie L. Gupton","doi":"10.1111/jnc.70002","DOIUrl":"10.1111/jnc.70002","url":null,"abstract":"<div>\u0000 \u0000 <p>The guidance cue netrin-1 promotes both growth cone attraction and growth cone repulsion. How netrin-1 elicits diverse axonal responses, beyond engaging the netrin receptor DCC and UNC5 family members, remains elusive. Here, we demonstrate that murine netrin-1 induces biphasic axonal responses in cortical neurons: Attraction at lower concentrations and repulsion at higher concentrations using both a microfluidic-based netrin-1 gradient and bath application of netrin-1. We find that repulsive turning in a netrin gradient is blocked by knockdown of UNC5C, whereas attractive turning is impaired by knockdown of DCC. TRIM9 is a brain-enriched E3 ubiquitin ligase previously shown to bind and cluster the attractive receptor DCC at the plasma membrane and regulate netrin-dependent attractive responses. However, whether TRIM9 also regulated repulsive responses to netrin-1 remained to be seen. In this study, we show that TRIM9 localizes and interacts with both the attractive netrin receptor DCC and the repulsive netrin receptor, UNC5C. We find that deletion of murine <i>Trim9</i> alters both attractive and repulsive axon turning and changes in growth cones size in response to murine netrin-1. TRIM9 was required for netrin-1-dependent changes in the surface levels of DCC and UNC5C in the growth cone during morphogenesis. We demonstrate that DCC at the membrane regulates the growth cone area and show that TRIM9 negatively regulates FAK activity in the absence of both repulsive and attractive concentrations of netrin-1. Together, our work demonstrates that TRIM9 interacts with and regulates both DCC and UNC5C during attractive and repulsive axonal responses to netrin-1.\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>\u0000 </div>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143059348","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}