Journal of Neurochemistry最新文献

{"title":"A Pharmacophore for Drugs Targeting the α4α4 Binding Site of the (α4)3(β2)2 Nicotinic Acetylcholine Receptor","authors":"Ali S. Kusay,&nbsp;Yujia Luo,&nbsp;Megan L. O'Mara,&nbsp;Thomas Balle","doi":"10.1111/jnc.70000","DOIUrl":"https://doi.org/10.1111/jnc.70000","url":null,"abstract":"<p>Neuronal nicotinic acetylcholine receptors (nAChRs) have an established role in pain pathways and devastating neurodegenerative diseases; however, few drugs have been successfully developed to target them. The most abundant nAChR in the brain, the α4β2 nAChR, is assembled from five subunits in a 3α:2β stoichiometry—(α4)₃(β2)₂. This receptor contains a unique agonist-binding site at the α4α4 interface in addition to two classical agonist-binding sites at α4β2 interfaces. Most known agonists target both α4α4 and α4β2 sites, however, a few compounds with selectivity for the α4α4 site have been identified. These α4α4 selective compounds have a modulator-like effect akin to benzodiazepines in the γ-aminobutyric acid type A receptor, which is desirable from a drug development perspective. The two most well characterised α4α4 selective compounds are CMPI and NS9283. Both are structurally very different from classical agonists, and it is puzzling how they occupy the same binding site. In the search for a common pharmacophore, we conducted extensive molecular dynamics simulations with both classical agonists and site-selective non-classical compounds. Analyses of the simulations revealed that the α4α4 binding site contains a unique pocket not found in the α4β2 binding site. CMPI and NS9283 were observed to bind in this pocket, thereby explaining why they are selective for the α4α4 binding site. The proposed binding mode featured a closed-loop C conformation, which is strongly correlated with agonism in nAChRs and explained key site-directed mutagenesis data for both compounds. Based on this binding mode, we proposed a pharmacophore for drugs targeting the α4α4 binding site. The proposed pharmacophore captures the essence of the original model, that is, nicotinic agonists act as a bridge between protein subunits. The pharmacophore model we propose is unique to the α4α4 binding site and provides a template for developing new site-selective therapeutic agents.\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":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.70000","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143438774","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":"In Vivo Assessment of Cortical Astrocyte Network Dysfunction During Autoimmune Demyelination: Correlation With Disease Severity","authors":"A. Moreno-García,&nbsp;R. Serrat,&nbsp;F. Julio-Kalajzic,&nbsp;A. Bernal-Chico,&nbsp;A. M. Baraibar,&nbsp;C. Matute,&nbsp;G. Marsicano,&nbsp;S. Mato","doi":"10.1111/jnc.16305","DOIUrl":"https://doi.org/10.1111/jnc.16305","url":null,"abstract":"<div>\u0000 \u0000 <p>Cortical damage and dysfunction is a pathological hallmark of multiple sclerosis (MS) that correlates with the severity of physical and cognitive disability. Astrocytes participate in MS pathobiology through a variety of mechanisms, and abnormal astrocytic calcium signaling has been pointed as a pathogenic mechanism of cortical dysfunction in MS. However, in vivo evidence supporting deregulation of astrocyte calcium-dependent mechanisms in cortical MS is still limited. Here, we applied fiber photometry to the longitudinal analysis of spontaneous and sensory-evoked astrocyte network activity in the somatosensory cortex of mice in an experimental autoimmune encephalomyelitis (EAE). We found that freely moving EAE mice exhibit spontaneously occurring astrocyte calcium signals of increased duration and reduced amplitude. Concomitantly, cortical astrocytes in EAE mice responded to sensory stimulation with calcium events of decreased amplitude. The emergence of aberrant astrocyte calcium signals in the somatosensory cortex paralleled the onset of neurological symptomatology, and changes in the amplitude of both spontaneous and evoked responses were selectively correlated to the severity of neurological deficits. These results highlight the imbalance of astrocyte network activity in the brain cortex during autoimmune inflammation and further support the relevance of astrocyte-based pathobiology as an underlying mechanism of cortical dysfunction in MS.\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":"2025-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143424215","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 Supramolecular Architecture of Mitochondrial Complex I in the Rat Brain Is Altered by Alzheimer's-Like Cerebral Amyloidosis","authors":"Gisela V. Novack,&nbsp;Pablo Galeano,&nbsp;Lucas A. Defelipe,&nbsp;Lorenzo Campanelli,&nbsp;Karen S. Campuzano,&nbsp;Cecilia Rotondaro,&nbsp;Eduardo M. Castaño,&nbsp;Sonia Do Carmo,&nbsp;A. Claudio Cuello,&nbsp;María M. García-Alai,&nbsp;Laura Morelli","doi":"10.1111/jnc.70017","DOIUrl":"https://doi.org/10.1111/jnc.70017","url":null,"abstract":"<div>\u0000 \u0000 <p>Mitochondrial respiratory complexes are organized into supercomplexes (SC) to regulate electron flow and mitigate oxidative stress. Alterations in SC organization in the brain may affect energy expenditure, oxidative stress, and neuronal survival. In this report, we investigated the amount, activity and organization of mitochondrial complex I (CI) in the hippocampus of 12-month-old McGill-R-Thy1-APP transgenic (Tg) rats, an animal model of Alzheimer's-like cerebral amyloidosis. By means of BN-PAGE, we found that the organization of SC did not differ between genotypes, but a lower abundance of SC was detected in Tg compared to wild-type (WT) rats. Using a more sensitive technique (2-D electrophoresis followed by Western blot), higher levels of free CI and a decrease in the relative abundance of assembled CI in SC (I-III₂ and I-III₂-IV) were observed in Tg rats. In-gel activity assays showed that the total activity of CI (CI + SC-CI) is lower in Tg compared to WT, while Tg samples show a significant decrease in SC-CI-associated activity. This alteration in CI assembly was associated with nitro-oxidative stress and changes in mitochondrial fusion-fission parameters. To assess CI composition, we applied LC–MS/MS to the isolated CI from BN-PAGE and found that 11 of 45 subunits described in mammals were found to be less abundant in Tg. We examined the levels of the nuclear-derived NDUFA9 subunit, which is critical for CI assembly, and found higher levels in the cytoplasmic fraction and lower levels in the mitochondrial fraction in Tg, suggesting that brain amyloidosis affects the import of CI subunits from the cytosol to the mitochondria, destabilizing the SC. This is the first report to characterize the types, abundance and activity of SC in the hippocampus of an animal model of cerebral amyloidosis, providing additional experimental evidence for the molecular mechanisms underlying the brain bioenergetic deficit characteristic of Alzheimer's disease.\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":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143404661","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":"Oxidative Stress Suppresses Trk Signaling While Stimulating JNK-Mediated Endocytosis and Cleavage of p75NTR: A Targetable Pathway for Neuroprotection in a Parkinson's Disease Model","authors":"Poshan V. Pokharel,&nbsp;Aaron M. Newchurch,&nbsp;Sunny C. Overby,&nbsp;Cassidy A. Spease,&nbsp;Isaac T. Perkins,&nbsp;Lorelei G. Darzi,&nbsp;Nabin Ghimire,&nbsp;Ahmed Lawan,&nbsp;Bradley R. Kraemer","doi":"10.1111/jnc.70010","DOIUrl":"https://doi.org/10.1111/jnc.70010","url":null,"abstract":"<div>\u0000 \u0000 <p>The p75 Neurotrophin Receptor (p75^NTR) is a multifunctional transmembrane protein that mediates neuronal responses to pathological conditions in specific regions of the nervous system. In many biological contexts, p75^NTR signaling is initiated through sequential cleavage of the receptor by α- and γ-secretases, which releases receptor fragments for downstream signaling. Our previous research demonstrated that proteolytic processing of p75^NTR in this manner is stimulated by oxidative stress in Lund Human Mesencephalic (LUHMES) cells, a dopaminergic neuronal cell line derived from human mesencephalic tissue. Considering the vulnerability of dopaminergic neurons in the ventral mesencephalon to oxidative stress and neurodegeneration associated with Parkinson's disease (PD), we investigated the role of this signaling cascade in neurodegeneration and explored cellular processes that govern oxidative stress-induced p75^NTR signaling. In the present study, we provide evidence that oxidative stress induces cleavage of p75^NTR by promoting c-Jun N-terminal Kinase (JNK)-dependent internalization of p75^NTR from the cell surface. This activation of p75^NTR signaling is counteracted by tropomyosin-related kinase (Trk) receptor signaling; however, oxidative stress leads to Trk receptor downregulation, thereby enhancing p75^NTR processing. Importantly, we demonstrate that this pathway can be inhibited by LM11a-31, a small molecule modulator of p75^NTR, thereby conferring protection against neurodegeneration. Treatment with LM11a-31 significantly reduced p75^NTR cleavage and neuronal death associated with oxidative stress. These findings reveal novel mechanisms underlying activation of p75^NTR in response to oxidative stress, underscore a key role for p75^NTR in dopaminergic neurodegeneration, and highlight p75^NTR as a potential therapeutic target for reducing neurodegeneration in PD.\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":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143389051","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":"Ganaxolone Reverses the Effect of Amyloid β-Induced Neurotoxicity by Regulating the Liver X Receptor Expression in APP Transfected SH-SY5Y Cells and Murine Model of Alzheimer's Disease","authors":"Divya,&nbsp;Mohammed Faruq,&nbsp;Sheikh Sana Nazir,&nbsp;Pooja Kaushik,&nbsp;Suhel Parvez,&nbsp;Divya Vohora","doi":"10.1111/jnc.70007","DOIUrl":"https://doi.org/10.1111/jnc.70007","url":null,"abstract":"<div>\u0000 \u0000 <p>Inhibiting β-amyloid aggregation and enhancing its clearance are the key strategies in Alzheimer's disease (AD) treatment. Liver X receptors (LXRs) plays a crucial role in cholesterol homeostasis and inflammation, and their activation can clear Aβ aggregates in AD. Allopregnanolone, a neurosteroid, positively influences AD through LXR regulation, while ganaxolone, its synthetic analog, is known for its neuroprotective properties. This study explores the effect of ganaxolone on LXR activation and regulation of genes involved in mitigating Aβ toxicity and tauopathy in SH-SY5Y cells transfected with APP695 Swe/Ind plasmid and an Aβ1–42 induced AD mouse model. Molecular docking stimulations indicated ganaxolone's binding and interaction with LXRβ. Subsequently, transfected neuronal cells exhibited increased mRNA levels of APP, TNF-α and IL-1β, decreased cell viability, reduced MMP and altered protein expression of Aβ, LXR, BCL-2, APOE, ABCA1, along with increased levels of mROS, Bax, and caspase 3 activity. Ganaxolone treatment significantly abrogated Aβ-induced effect in transfected neuronal cells by enhancing LXRβ expression, inducing LXR:RXR colocalization, thereby increasing APOE and ABCA1 expression. It also decreased tau mRNA levels in transfected cells. Importantly, in AD mice, ganaxolone ameliorated cognitive impairment, reduced Aβ toxicity, tau levels, and neuroinflammatory markers, restored mitochondrial function, and decreased neuronal apoptosis. Taken together, these novel results highlight the central role of LXR in mediating Aβ-induced toxicity and provide preclinical evidence for ganaxolone as a potential agent to reduce toxicity in an LXR-dependent manner. This may serve as a promising treatment strategy to slow or prevent neurodegeneration in AD patients.\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":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143389047","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":"Hunger Games: A Modern Battle Between Stress and Appetite","authors":"Whitnei Smith,&nbsp;Estefania P. Azevedo","doi":"10.1111/jnc.70006","DOIUrl":"https://doi.org/10.1111/jnc.70006","url":null,"abstract":"<p>Stress, an evolutionarily adaptive mechanism, has become a pervasive challenge in modern life, significantly impacting feeding-relevant circuits that play a role in the development and pathogenesis of eating disorders (EDs). Stress activates the hypothalamic–pituitary–adrenal (HPA) axis, disrupts specific neural circuits, and dysregulates key brain regions, including the hypothalamus, hippocampus, and lateral septum. These particular structures are interconnected and key in integrating stress and feeding signals, modulating hunger, satiety, cognition, and emotional coping behaviors. Here we discuss the interplay between genetic predispositions and environmental factors that may exacerbate ED vulnerability. We also highlight the most commonly used animal models to study the mechanisms driving EDs and recent rodent studies that emphasize the discovery of novel cellular and molecular mechanisms integrating stress and feeding signals within the hippocampus–lateral septum–hypothalamus axis. In this review, we discuss the role of gut microbiome, an emerging area of research in the field of EDs and unanswered questions that persist and hinder the scientific progress, such as why some individuals remain resilient to stress while others become at high risk for the development of EDs. We finally discuss the need for future research delineating the impact of specific stressors on neural circuits, clarifying the relevance and functionality of hippocampal–septal–hypothalamic connectivity, and investigating the role of key neuropeptides such as CRH, oxytocin, and GLP-1 in human ED pathogenesis. Emerging tools like single-cell sequencing and advanced human imaging could uncover cellular and circuit-level changes in brain areas relevant for feeding in ED patients. Ultimately, by integrating basic and clinical research, science offers promising avenues for developing personalized, mechanism-based treatments targeting maladaptive eating behavior for patients suffering from EDs.\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":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.70006","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143389050","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":"Direct Current Stimulation (DCS) Modulates Lipid Metabolism and Intercellular Vesicular Trafficking in SHSY-5Y Cell Line: Implications for Parkinson's Disease","authors":"Marco Piccoli,&nbsp;Luisa Barbato,&nbsp;Natale Vincenzo Maiorana,&nbsp;Alessandra Mingione,&nbsp;Francesca Raimondo,&nbsp;Marco Ghirimoldi,&nbsp;Federica Cirillo,&nbsp;Mattia Schiepati,&nbsp;Domenico Salerno,&nbsp;Luigi Anastasia,&nbsp;Elisabetta Albi,&nbsp;Marcello Manfredi,&nbsp;Tommaso Bocci,&nbsp;Alberto Priori,&nbsp;Paola Signorelli","doi":"10.1111/jnc.70014","DOIUrl":"https://doi.org/10.1111/jnc.70014","url":null,"abstract":"<p>The modulation of the brain's electrical activity for therapeutic purposes has recently gained attention, supported by the promising results obtained through the non-invasive application of transcranial direct current stimulation (tDCS) in the treatment of neurodegenerative and neurological diseases. To optimize therapeutic efficacy, it is crucial to investigate the cellular and molecular effects of tDCS. This will help to identify important biomarkers, predict patient's response and develop personalized treatments. In this study, we applied direct current stimulation (DCS) to a neural cell line, using mild currents over short periods of time (0.5 mA, 20 min), with 24-h intervals. We observed that DCS induced changes in the cellular lipidome, with transient effects observed after a single stimulation (lasting 24 h) and more significant, long-lasting effects (up to 72 h) after repeated stimulation cycles. In neural cells, multiple DCS treatment modulated structural membrane lipids (PE, PS, PI), downregulated glycerol lipids with ether-linked fatty acids and pro-inflammatory lipids (ceramides and lyso-glycerophospholipids) (<i>p</i> ≤ 0.005). Multiple DCS sessions altered transcriptional activity by decreasing the expression of inflammatory cytokines (TNF-α, <i>p</i> ≤ 0.05; IL-1β, <i>p</i> ≤ 0.01), while increasing the expression of neuroprotective factors such as heme oxygenase-1 (<i>p</i> ≤ 0.0001) and brain-derived neurotrophic factor (<i>p</i> ≤ 0.05), as well as proteins involved in vesicular transport (SNARE, sorting nexins and seipin and α-synuclein; <i>p</i> ≤ 0.05). In addition, DCS enhanced the release of extracellular vesicles, with repeated stimulations significantly increasing the release of exosomes threefold. In conclusion, while a single electrical stimulation induces transient metabolic changes with limited phenotypic effects, repeated applications induce a broader and deeper modulation of lipid species. This may lead to a neuroprotective and neuroplasticity-focussed transcriptional profile, potentially supporting the therapeutic effects of tDCS at the cellular and molecular level in patients..\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":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.70014","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143380204","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":"PPARβ/δ Activation Improves Corticosterone-Induced Oxidative Stress Damage in Astrocytes by Targeting UBR5/ATM Signaling","authors":"Juan Ji,&nbsp;Ye-Fan Chen,&nbsp;Chen Hong,&nbsp;Xue-Wei Ren,&nbsp;Hang Xu,&nbsp;Zhen-Yu Cai,&nbsp;Yin-Feng Dong,&nbsp;Xiu-Lan Sun","doi":"10.1111/jnc.70013","DOIUrl":"https://doi.org/10.1111/jnc.70013","url":null,"abstract":"<div>\u0000 \u0000 <p>Oxidative stress-mediated astrocytic damage contributes to nerve injury and the development of depression, especially under stress conditions. Peroxisomes and pexophagy are essential for balancing oxidative stress and protein degradation products. Our previous findings suggest that peroxisome proliferators-activated receptor β/δ (PPARβ/δ) activation significantly alleviates depressive behaviors by preventing astrocytic injury. However, the underlying mechanisms remain unclear. In the present study, we established oxidative injury by treating astrocytes with corticosterone. Subsequently, PPARβ/δ agonists and antagonists were applied to determine the effects of PPARβ/δ on balancing peroxisomes and pexophagy in astrocytes. The PPARβ/δ agonist (GW0742) significantly improved cell viability and decreased intracellular reactive oxygen species (ROS) production induced by corticosterone, while pretreatment with the PPARβ/δ, antagonist GSK3787 reversed the effects of GW0742. Moreover, activating PPARβ/δ promoted peroxisomal biogenesis factor 5 (PEX5)-mediated pexophagy by enhancing the phosphorylation of ataxia-telangiectasia mutated (ATM) kinase. Conversely, blocking PPARβ/δ with GSK3787 partially abolished the effects of GW0742. Further investigations demonstrated that activation of PPARβ/δ not only induced transcription of the ubiquitin protein ligase E3 component n-recognin 5 (UBR5) but also enhanced the interaction between PPARβ/δ and UBR5, contributing to ATM interactor (ATMIN) degradation, and increased phosphorylated ATM kinase levels. Therefore, this study revealed that activating PPARβ/δ improves corticosterone-induced oxidative damage in astrocytes by enhancing pexophagy. PPARβ/δ directly interacts with UBR5 to facilitate ATMIN degradation and promotes ATM phosphorylation, thereby maintaining the balance between peroxisomes and pexophagy. These findings suggest that PPARβ/δ is a potential target for promoting pexophagy in astrocytes upon stress.\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":"2025-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143362858","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":"mTORC2 Regulates Actin Polymerization in Auditory Cells","authors":"Michael Lanz,&nbsp;Maurizio Cortada,&nbsp;Yu Lu,&nbsp;Soledad Levano,&nbsp;Daniel Bodmer","doi":"10.1111/jnc.70012","DOIUrl":"https://doi.org/10.1111/jnc.70012","url":null,"abstract":"<div>\u0000 \u0000 <p>Mammalian target of rapamycin complex 2 (mTORC2) is essential for hearing by regulating auditory hair cell structure and function. However, mechanistic details of how mTORC2 regulates intracellular processes in sensory hair cells have not yet been clarified. To further elucidate the role of mTORC2 in auditory cells, we generated a <i>Rictor</i> knockout cell line from HEI-OC1 auditory cells. mTORC2-deficient auditory cells exhibited significant alterations in actin cytoskeleton morphology and decreased proliferation rates. Additionally, we observed a reduction in phosphorylation of protein kinase C alpha (PKCα) and disrupted actin polymerization in mTORC2-deficient cells. Using proteomics, we found that mTORC2 disruption altered expression of cytoskeleton-related proteins in auditory cells. These findings provide valuable mechanistic insights into the functional role of mTORC2 in auditory cells, potentially opening new perspectives to address sensorineural hearing loss.\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":"2025-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143362859","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":"Genetic Markers of Postmortem Brain Iron","authors":"Marilyn C. Cornelis,&nbsp;Amir Fazlollahi,&nbsp;David A. Bennett,&nbsp;Julie A. Schneider,&nbsp;Scott Ayton","doi":"10.1111/jnc.16309","DOIUrl":"https://doi.org/10.1111/jnc.16309","url":null,"abstract":"<p>Brain iron (Fe) dyshomeostasis is implicated in neurodegenerative diseases. Genome-wide association studies (GWAS) have identified plausible loci correlated with peripheral levels of Fe. Systemic organs and the brain share several Fe regulatory proteins but there likely exist different homeostatic pathways. We performed the first GWAS of inductively coupled plasma mass spectrometry measures of postmortem brain Fe from 635 Rush Memory and Aging Project (MAP) participants. Sixteen single nucleotide polymorphisms (SNPs) associated with Fe in at least one of four brain regions were measured (<i>p</i> &lt; 5 × 10⁻⁸). Promising SNPs (<i>p</i> &lt; 5 × 10⁻⁶) were followed up for replication in published GWAS of blood, spleen, and brain imaging Fe traits and mapped to candidate genes for targeted cortical transcriptomic and epigenetic analysis of postmortem Fe in MAP. Results for SNPs previously associated with other Fe traits were also examined. Ninety-eight SNPs associated with postmortem brain Fe were at least nominally (<i>p</i> &lt; 0.05) associated with one or more related Fe traits. Most novel loci identified had no direct links to Fe regulatory pathways but rather endoplasmic reticulum-Golgi trafficking (<i>SORL1, SORCS2, MARCH1, CLTC</i>), heparan sulfate (<i>HS3ST4, HS3ST1</i>), and coenzyme A (<i>SLC5A6, PANK3</i>); supported by nearest gene function and omic analyses. We replicated (<i>p</i> &lt; 0.05) several previously published Fe loci mapping to candidate genes in cellular and systemic Fe regulation. Finally, novel loci (<i>BMAL, COQ5, SLC25A11</i>) and replication of prior loci (<i>PINK1, PPIF, LONP1</i>) lend support to the role of circadian rhythms and mitochondria function in Fe regulation more generally. In summary, we provide support for novel loci linked to pathways that may have greater relevance to brain Fe accumulation; some of which are implicated in neurodegeneration. However, replication of a subset of prior loci for blood Fe suggests that genetic determinants or biological pathways underlying Fe accumulation in the brain are not completely distinct from those of Fe circulating in the periphery.\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":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.16309","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143362465","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}