Neurochemical Research最新文献

{"title":"JAK2/STAT3 Signaling Pathway Modulates Acute Methylmercury Toxicity in the Mouse Astrocyte C8-D1A Cell Line","authors":"Aafia Ahmed,&nbsp;Maximus Wong,&nbsp;Abel Santamaria,&nbsp;João Batista Rocha,&nbsp;Aaron B Bowman,&nbsp;Michael Aschner,&nbsp;Beatriz Ferrer","doi":"10.1007/s11064-025-04507-7","DOIUrl":"10.1007/s11064-025-04507-7","url":null,"abstract":"<div><p>Methylmercury (MeHg), an environmental pollutant, reaches the human body predominantly through contaminated fish consumption, potentially leading to severe neurological disorders. Upon ingestion MeHg reaches the brain and selectively accumulates in astrocytes. The activation of nuclear factor erythroid 2-related factor 2 (Nrf2) has been identified as a key early response to MeHg-induced oxidative injury, positioning it as a potential therapeutic target. However, recent studies suggest that Nrf2 activation alone may not be sufficient to mitigate MeHg toxicity, indicating the existence of other protective mechanisms. The signal transducer and activator of transcription 3 (STAT3) signaling pathway, known for its role in cell growth and survival, has emerged as a potential player in redox homeostasis. In this study, we investigated the role of STAT3 in acute (≤ 24 h) MeHg-induced neurotoxicity. MeHg exposure induced STAT3 expression in C8-D1A astrocytic cells. Our data demonstrated that pharmacological inhibition of STAT3 using AG490 or C188-9 exacerbated MeHg-induced cell death and compromised antioxidant responses. Furthermore, to fully characterize the role of STAT3 in oxidative stress, we used two different antioxidants, N-acetylcysteine (NAC) and Trolox. Conversely, reactive oxygen species (ROS)-scavenging antioxidants partially ameliorated STAT3 activation, suggesting that MeHg-induced STAT3 activation is mediated, at least in part, by mechanisms independent of ROS. Our findings suggest that STAT3 contributes to neuroprotection against MeHg exposure in astrocytes and is, at least in part, regulated by the increase in ROS levels within these cells.</p></div>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":"50 4","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s11064-025-04507-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144832033","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":"Biological Characterization of the Anti-ferroptotic Properties of a Novel Anti-Parkinsonian Iron (II) Selective Dopamine Agonist, D-583","authors":"Vibha Deshpande,&nbsp;Kevin Schick,&nbsp;Purba Mazumder,&nbsp;Aloke K. Dutta","doi":"10.1007/s11064-025-04508-6","DOIUrl":"10.1007/s11064-025-04508-6","url":null,"abstract":"<div><p>Here, we report the in vitro and in vivo characterization of a novel hybrid D2/D3 agonist and iron (II)-specific chelator, D-583, as a multi-target-directed ligand for Parkinson’s disease (PD). In our previously published work, we demonstrated that D-583 is a potent agonist of dopamine (DA) D2/D3 receptors. In this study, we show that D-583 is an efficacious brain-penetrant compound, exhibiting efficacy in a PD symptomatic animal model. As further evidence of its potential as a neuroprotective agent in PD, the current study reveals that D-583 protects neuronal PC12 cells from 6-OHDA toxicity. Moreover, the compound was found to exhibit anti-ferroptotic activity against RSL3-induced cell death in PANC-1 cell lines. Potent antioxidant activity and mitochondrial membrane potential stabilization were also observed under ferroptotic conditions induced by RSL3. Finally, mechanistic evaluation of its anti-ferroptotic properties revealed the restoration of key ferroptosis-related proteins, including GPX4, SLC7A11, and NRF2, following RSL3 treatment. Our findings establish the potent anti-ferroptotic properties of the brain-penetrant iron (II) chelator and dopamine agonist, D-583. Given that ferroptosis is implicated in PD, compounds like D-583 could serve as potential neuroprotective and symptomatic therapeutic agents for PD.</p></div>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":"50 4","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144832034","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":"Ameliorative Role of Phosphodiesterase-5 (PDE-5) Inhibitor “Avanafil” via Modulating cAMP & cGMP Pathway Against Alzheimer’s Disease","authors":"Mohd Talib,&nbsp;Nazia Siddiqui,&nbsp;Prabhash Nath Tripathi,&nbsp;Ankit Chaudhary","doi":"10.1007/s11064-025-04516-6","DOIUrl":"10.1007/s11064-025-04516-6","url":null,"abstract":"<div><p>Alzheimer’s disease (AD) is the utmost age-linked neuro-degenerative conditions, marked via gradual deterioration of cognitive abilities and continues to be a significant worldwide health issue. Etiology of AD is linked to neurobehavioral variations, deposition of Aβ, p-Tau, activations of glycogen synthase kinase-3 (GSK-3β), and fluctuations in cyclic nucleotides including cAMP &amp; cGMP. As per evidence, PDE-5 inhibitors are able to boost cAMP &amp; cGMP levels and other etiological hallmarks, which could be a novel AD cure. The main objective of present study was to examine therapeutic potential of Avanafil in a rat model of AD induced by administering 60 mg/kg of D-galactose (D-galac) and 10 mg/kg of Aluminium chloride (AlCl₃) for a period of 42 days. Following this, 28 days of therapy with two different doses of Avanafil (3 mg/kg and 6 mg/kg) was given. Towards end of treatment, locomotor activity &amp; Morris water maze were performed. Rats were then euthanized and hippocampus was isolated for biochemical parameters &amp; histological investigation. Results revealed that both neurobehavioral parameters exhibits significant difference in treatment group as compared to toxic group. Alterations in level of AchE, Aβ (1–42), GSK-3β, p-Tau, tumor necrosis factor- alpha (TNF-α), IL-1β, &amp; IL-6, cAMP, cGMP &amp; BDNF, and oxidative stress were significantly reversed towards normal level in the treatment group when compared to toxic rats. Histopathological changes by H&amp;E staining showed significant difference in treatment vs. toxic rats. The current investigation suggested that Avanafil improves memory by improving cAMP and cGMP pathways, implying that it may have therapeutic prospective in cognitive deficiencies linked with Alzheimer’s disease.</p></div>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":"50 4","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144832030","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":"O-GlcNAcylation Suppressed Apoptosis and Ferroptosis in Traumatic Brain Injury by Enhancing Mitophagy","authors":"Li Zhang,&nbsp;Maoxin Fei,&nbsp;Yaonan Peng,&nbsp;Tao Li,&nbsp;Xiangjun Ji,&nbsp;Jinqi Gao,&nbsp;Mi Tian","doi":"10.1007/s11064-025-04519-3","DOIUrl":"10.1007/s11064-025-04519-3","url":null,"abstract":"<div><p>O-linked-N-acetylglucosaminylation (O-GlcNAcylation), a distinctive post-translational modification (PTM), is ubiquitously present in numerous nuclear and mitochondrial proteins. The emerging role of O-GlcNAcylation is increasingly recognized for its involvement in various diseases. However, its role in traumatic brain injury (TBI) has not been explored. This study was aimed to explore the neuroprotection of O-GlcNAcylation in both in vivo and in vitro TBI models. Our results revealed that the levels of O-GlcNAcylation were increased after TBI. Up-regulation of O-GlcNAcylation by Thiamet G (TMG) provided neuroprotection after TBI. Moreover, TMG inhibited TBI-triggered blood-brain barrier (BBB) damage. Furthermore, TMG alleviated apoptosis and ferroptosis caused by TBI. Besides, TMG activated mitophagy after TBI, and the neuroprotection of TMG was attenuated when mitophagy was inhibited. Importantly, TMG also attenuated cell death, decreased apoptosis and ferroptosis, and activated mitophagy after TBI in vitro. Taken together, our data provided the first evidence that O-GlcNAcylation played a crucial role in TBI by activation of mitophagy.</p></div>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":"50 4","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144832181","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":"Comparative Molecular Dynamics Reveals How LRRK2 Inhibitors Distinguish G2019S from Wild-Type","authors":"Chuancheng Wei,&nbsp;Choon Han Heh,&nbsp;Lei Cheng Lit,&nbsp;Sek Peng Chin","doi":"10.1007/s11064-025-04520-w","DOIUrl":"10.1007/s11064-025-04520-w","url":null,"abstract":"<p>Leucine-rich repeat kinase 2 (LRRK2) has become a critical drug target in Parkinson’s disease, with mutation-selective inhibitors offering promising potential for precision medicine. However, the structural similarity between G2019S and wild-type kinases presents a significant challenge in developing selective inhibitors. Although recent advances have led to inhibitors that selectively target G2019S or wild-type kinases, the selectivity mechanism of these inhibitors remains unclear. We employed molecular dynamics simulations to investigate and explore kinase-ligand interactions and identify the underlying mechanisms of selectivity. The results suggest that ligand binding drives the conformational changes, which is a key contributing factor to selectivity, rather than the strength of the ligand binding. The ligand-induced conformational changes lead to kinase destabilisation and inactivation. Additionally, key residues, such as Tyr2018 and Asp2017, were found to play pivotal roles in the selectivity. These insights underscore the importance of incorporating conformational dynamics into the design of future LRRK2 mutant-selective inhibitors.</p>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":"50 4","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s11064-025-04520-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144832028","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":"Electroacupuncture Protects Against Post-stroke Cognitive Impairment by Promoting an IL-33/ST2 Axis-Mediated Microglia M2 Polarization","authors":"Yuhan Zhang,&nbsp;Zhimin Ding,&nbsp;Yamin Wang,&nbsp;Hao Liu,&nbsp;Jing Gao,&nbsp;Huiling Wang,&nbsp;Mingli Wu,&nbsp;Xiaodong Feng,&nbsp;Xin Shen","doi":"10.1007/s11064-025-04522-8","DOIUrl":"10.1007/s11064-025-04522-8","url":null,"abstract":"<div><p>Post-stroke cognitive impairment (PSCI) is a common and debilitating complication of stroke that significantly hinders rehabilitation. Electroacupuncture (EA), which integrates traditional acupuncture with electrical stimulation, has been widely applied in clinical practice and shown remarkable efficacy in treating PSCI. However, its underlying mechanisms remain largely unexplored. The PSCI rat model was established by middle cerebral artery occlusion/reperfusion (MCAO/R). EA treatment commenced 24 h after reperfusion and was administered daily for two weeks. To investigate the role of the Interleukin-33 (IL-33)/Interleukin 1 Receptor-Like 1 (ST2) signaling pathway in EA’s therapeutic effects, the ST2 inhibitor Astegolimab (Anti-ST2) was stereotactically injected into the lateral ventricle prior to EA intervention. Neurological function was evaluated using the Zea-Longa neurological deficit score, while emotional and cognitive behaviors were assessed through the open field test (OFT) and novel object recognition (NOR) test. Cerebral infarct volume was quantified using 2,3,5-triphenyltetrazolium chloride (TTC) staining. Protein expression in the striatum was analyzed by Western blotting and immunofluorescence staining, and structural alterations were examined using hematoxylin–eosin (HE) staining. Microglial polarization in the ischemic penumbra was evaluated via double immunofluorescence staining. Serum levels of inflammatory cytokines, including interleukin (IL)-33, IL-10, IL-4, TNF-α, IL-1β, and IL-6, were determined using enzyme-linked immunosorbent assay (ELISA). EA markedly enhanced learning and memory in stroke rats, upregulated IL-33 expression, promoted M2 microglial polarization, and preserved the integrity of brain white matter. However, blockade of the IL-33/ST2 pathway with Anti-ST2 diminished the therapeutic benefits of EA, aggravated white matter injury and cerebral infarct volume, and amplified the inflammatory response. EA facilitates microglial polarization toward the M2 phenotype via the IL-33/ST2 signaling pathway, strengthens the structural integrity of cerebral white matter, and promotes neurological recovery after ischemic stroke.</p></div>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":"50 4","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144832027","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":"Histamine H3 Receptor Antagonists Influence the Directional Growth of Type II Spiral Ganglion Neurites Within the Developing Cochlea of C57BL/6 Mice","authors":"Lingyi Kong,&nbsp;Heidi Olze,&nbsp;Agnieszka J. Szczepek","doi":"10.1007/s11064-025-04521-9","DOIUrl":"10.1007/s11064-025-04521-9","url":null,"abstract":"<div><p>The histamine H3 receptor (H3R) is a crucial regulator of synaptic plasticity, neurotransmitter release, and neural signaling within the central nervous system. However, its role in the cochlea remains poorly understood, even though mast cells, a rich endogenous source of histamine, have recently been documented in the mammalian cochlea. This study examined H3R expression and localization in the postnatal day 4–5 (P4-5) C57BL/6 mouse cochlea and evaluated its functional consequences under antagonist treatment. RT-qPCR analysis showed significantly higher <i>H3R</i> mRNA levels in the modiolus compared to the organ of Corti and the lateral wall. Immunofluorescence staining confirmed H3R localization in hair cells (HCs) and spiral ganglion neurons (SGNs). Dissected cochlear explants exposed to two distinct H3R antagonists—ciproxifan and pitolisant—at concentrations of 10µM, 50µM, and 100µM, displayed different responses: ciproxifan induced dose-dependent HC loss. In contrast, pitolisant caused no loss of HC but led to stereociliary abnormalities at higher concentrations. Both antagonists disrupted type II SGN neurite projections, redirecting their normal basal-directed trajectory toward the apical region. These findings implicate H3R in maintaining cochlear structural integrity and guiding SGN neurite development during early postnatal maturation. Further investigation into H3R-mediated mechanisms may reveal new therapeutic targets for hearing preservation and repair.</p></div>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":"50 4","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s11064-025-04521-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144832031","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":"Sex-Specific Properties of Astrocytes: From Development to Evolutionary Insights","authors":"Mariza Bortolanza,&nbsp;Davide Gobbo,&nbsp;Lipao Fang,&nbsp;Anja Scheller,&nbsp;Xianshu Bai,&nbsp;Frank Kirchhoff","doi":"10.1007/s11064-025-04512-w","DOIUrl":"10.1007/s11064-025-04512-w","url":null,"abstract":"<div><p>Exploring sex-specific differences in astrocytes has emerged as a vital area of neurobiological research. This research sheds light on how astrocytes in females and males differ in their contribution to neuronal functionality, overall brain health, and various neurological disorders. These cells play a critical role in sustaining homeostasis, providing metabolic support, facilitating neurotransmitter recycling and responding to injuries to the central nervous system. Their physiology exhibits significant variability, which is influenced by factors such as sex, developmental stage, species differences and environmental conditions. This review provides an integrated overview of these factors, addressing key themes including developmental dynamics, aging, signalling mechanisms, glial interactions, responses to pathological states and cross-species comparisons.</p></div>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":"50 4","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s11064-025-04512-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144832035","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":"Targeting IDO1 in Huntington’s Disease: Network Pharmacology and Preclinical Evidence from Coffea arabica","authors":"Vishnu Kumar Malakar,&nbsp;Dhritiman Roy,&nbsp;Chandi C. Malakar,&nbsp;Yogesh Mahadu Khetmalis,&nbsp;Pratap Chand Mali,&nbsp;Nitesh Kumar Poddar","doi":"10.1007/s11064-025-04509-5","DOIUrl":"10.1007/s11064-025-04509-5","url":null,"abstract":"<p>Huntington’s disease (HD) is a hereditary neurodegenerative disorder characterized by involuntary motor dysfunction and progressive cognitive impairment. This study aimed to explore the therapeutic potential of <i>Coffea arabica</i> (CA) phytoconstituents using a network pharmacology-based drug repurposing approach. CA-related Phytoconstituents were identified from public databases, while HD-related targets were retrieved from the DisGeNET database. Indoleamine 2,3-dioxygenase (IDO1) and huntingtin (HTT) were identified as two common overlapping targets using Venny 2.1. Protein–protein interaction (PPI) networks were constructed by CytoScape software. Gene ontology (GO) and KEGG pathway enrichment analysis, followed by MCODE and ClueGO software, revealed IDO1, HTT, PPAR-γ, ESR1, and CASP3 as key targets in HD pathogenesis. Among CA phytoconstituents, geraniol was selected based on its high binding affinity to IDO1 (PDB: 6V52), with a docking score of–8.01 kcal/mol compared to–4.39 kcal/mol for the reference inhibitor. Density functional theory (DFT) analysis showed a dipole moment of 2.50 Debye. Molecular dynamics simulations confirmed the stability of the IDO1–geraniol complex, with key interactions involving Ser167. In a 3-nitropropionic acid (3-NP)-induced HD animal model, geraniol (15 mg/kg) significantly improved motor function and cognitive performance, reduced lipid peroxidation and nitrite levels, and restored the activities of antioxidant enzymes (SOD, GSH, catalase). Neurotransmitter alterations (GABA, DA, glutamate, AChE) were also regulated. Histological studies revealed preservation of striatal neurons. These findings suggest that geraniol exerts neuroprotective effects in HD via modulation of IDO1 activity, oxidative stress, and neurotransmitter balance.</p><p>This study integrates network pharmacology, in silico modeling, and in vivo analysis to explore geraniol, a key metabolite of <i>Coffea arabica</i>, as a multi-target agent for Huntington’s disease (HD). Geraniol showed strong binding to IDO1, restored cognitive and motor functions, balanced oxidative stress, and preserved striatal neurons in an HD rat model. Our findings suggest geraniol as a promising therapeutic candidate through modulation of IDO1, redox balance, and neurotransmitters.</p>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":"50 4","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144832299","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":"TDAG51 Mediates Negative Signaling Crosstalk Between NGF/p75NTR-Induced Cell Death and GDNF/RET-Promoted Survival in Motor Neuron-Derived Cells","authors":"Fernando Federicci,&nbsp;Fernanda Ledda,&nbsp;Gustavo Paratcha","doi":"10.1007/s11064-025-04518-4","DOIUrl":"10.1007/s11064-025-04518-4","url":null,"abstract":"<div><p>GDNF is a potent survival and differentiation factor for motor neurons and other central and peripheral neuronal populations. While the signaling pathways by which GDNF promotes survival/differentiation have been relatively well established, the molecular mechanisms that restrict its biological effects remain unclear. In this study, we show that TDAG51 plays a role in regulating the GDNF-induced PI3K/AKT survival pathway. Our findings demonstrate that treatment of motor neuron-derived MN1 cells with high levels of nerve growth factor (NGF), a treatment that under oxidative conditions promotes p75 neurotrophin receptor (p75^NTR)-dependent motor neuron apoptosis, induces TDAG51, which in turn inhibits GDNF/RET-mediated AKT signaling. Moreover, knockdown of <i>Tdag51</i> potentiates the ability of GDNF to activate AKT and provides protection against NGF-induced p75^NTR-dependent cell death in MN1 cells. Mechanistically, short-term GDNF stimulation of MN1 cells expressing high levels of TDAG51 promotes the translocation and recruitment of TDAG51 into detergent-resistant plasma membrane microdomains via a PI3K-dependent mechanism. The NGF/p75^NTR signaling-induced increase in TDAG51 levels antagonizes AKT activation triggered by GDNF/RET signaling, likely by interfering with AKT´s interaction with PIP3. Taken together, our results demonstrate that TDAG51 is a key mediator of the balance between NGF-induced p75^NTR-promoted apoptotic pathway and GDNF/RET-mediated survival signaling in MN1 neuronal cells.</p></div>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":"50 4","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144832029","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}