Journal of Neurochemistry最新文献

{"title":"Neuroglial Advances: New Roles for Established Players","authors":"Alexei Verkhratsky,&nbsp;Baoman Li,&nbsp;Jianqin Niu,&nbsp;Si-Si Lin,&nbsp;Yixun Su,&nbsp;Wei-Na Jin,&nbsp;Yifan Li,&nbsp;Shihe Jiang,&nbsp;Chenju Yi,&nbsp;Fu-Dong Shi,&nbsp;Yong Tang","doi":"10.1111/jnc.70080","DOIUrl":"https://doi.org/10.1111/jnc.70080","url":null,"abstract":"<p>Neuroglial cells perform numerous physiological functions and contribute to the pathogenesis of all diseases of the nervous system. Neuroglial neuroprotection defines the resilience of the nervous tissue to exo- and endogenous pathological challenges, while neuroglial defence determines the progression and outcome of neurological disorders. IN this paper, we overview previously unknown but recently discovered roles of various types of neuroglial cells in diverse physiological and pathological processes. First, we describe the role of ependymal glia in the regulation of cerebrospinal fluid flow from the spinal cord to peripheral tissues through the spinal nerves. This newly discovered pathway provides a highway for the CNS–body volume transmission. Next, we present the mechanism by which astrocytes control migration and differentiation of oligodendrocyte precursor cells (OPCs). In pre- and early postnatal CNS, OPCs migrate using vasculature (which is yet free from glia limitans perivascularis) as a pathfinder. Newly forming astrocytic perivascular endfeet signal (through semaphorin-plexin cascade) to OPCs that detach from the vessels and start to differentiate into myelinating oligodendrocytes. We continue the astrocyte theme by demonstrating the neuroprotective role of APOE-laden astrocytic extracellular vesicles in neuromyelitis optica. Next, we explore the link between astrocytic morphology and stress-induced depression. We discuss the critical role of astrocytic ezrin, the cytosolic linker defining terminal astrocyte arborisation and resilience to stress: overexpression of ezrin in prefrontal cortical astrocytes makes mice resistant to stress, whereas ezrin knockdown increases animals vulnerability to stress. Subsequently, we highlight the pathophysiological role of oligodendroglial lineage in schizophrenia by describing novel hypertrophied OPCs in the post-mortem patient's tissue and in a mouse model with OPCs overexpressing alternative splice variant DISC1-Δ3. These DISC1-Δ3-OPCs demonstrated overactivated Wnt/β-catenin signalling pathway and were sufficient to trigger pathological behaviours. Finally, we deliberate on the pathological role of astrocytic and microglial connexin 43 hemichannels in Alzheimer's disease and present a new formula of Cx43 hemichannel inhibitor with increased blood–brain barrier penetration and brain retention.\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 5","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.70080","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143950246","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":"Proteomics Analysis of the TDP-43 Interactome in Cellular Models of ALS Pathogenesis","authors":"Flora Cheng,&nbsp;Tyler Chapman,&nbsp;Juliana Venturato,&nbsp;Jennilee M. Davidson,&nbsp;Stella A. Polido,&nbsp;Livia Rosa-Fernandes,&nbsp;Rebecca San Gil,&nbsp;Hannah J. Suddull,&nbsp;Selina Zhang,&nbsp;Chiara Y. Macaslam,&nbsp;Paulina Szwaja,&nbsp;Roger Chung,&nbsp;Adam K. Walker,&nbsp;Stephanie L. Rayner,&nbsp;Marco Morsch,&nbsp;Albert Lee","doi":"10.1111/jnc.70079","DOIUrl":"https://doi.org/10.1111/jnc.70079","url":null,"abstract":"<p>Cytoplasmic aggregation and nuclear depletion of TAR DNA-binding protein 43 (TDP-43) is a hallmark pathology of several neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD) and limbic-predominant age-related TDP-43 encephalopathy (LATE). However, the protein interactome of TDP-43 remains incompletely defined. In this study, we aimed to identify putative TDP-43 protein partners within the nucleus and the cytoplasm and with different disease models of TDP-43 by comparing TDP-43 interaction partners in three different cell lines. We verified the levels of interaction of protein partners under stress conditions as well as after introducing TDP-43 variants containing ALS missense mutations (G294V and A315T). Overall, we identified 58 putative wild-type TDP-43 interactors, including novel binding partners responsible for RNA metabolism and splicing. Oxidative stress exposure broadly led to changes in TDP-43^WT interactions with proteins involved in mRNA metabolism, suggesting a dysregulation of the transcriptional machinery early in disease. Conversely, although G294V and A315T mutations are both located in the C-terminal domain of TDP-43, both mutants presented different interactome profiles with most interaction partners involved in translational and transcriptional machinery. Overall, by correlating different cell lines and disease-simulating interventions, we provide a list of high-confidence TDP-43 interaction partners, including novel and previously reported proteins. Understanding pathological changes to TDP-43 and its specific interaction partners in different models of stress is critical to better understand TDP-43 proteinopathies and provide novel potential therapeutic targets and biomarkers.\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 5","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.70079","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143944642","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":"Evaluation of the Alterations in Central Cholinergic Neurotransmission in Aging and Amyloid Precursor Protein Knock-In Mice","authors":"Itsumi Nagai-Arakawa,&nbsp;Ikunobu Muramatsu,&nbsp;Junsuke Uwada,&nbsp;Yo Tsuda,&nbsp;Akinori Tokunaga,&nbsp;Ai Irie,&nbsp;Hideyuki Maeda,&nbsp;Yuta Madokoro,&nbsp;Toyohiro Sato,&nbsp;Yuto Uchida,&nbsp;Takashi Saito,&nbsp;Takaomi C. Saido,&nbsp;Kiyonao Sada,&nbsp;Takayoshi Masuoka,&nbsp;Noriyuki Matsukawa","doi":"10.1111/jnc.70081","DOIUrl":"https://doi.org/10.1111/jnc.70081","url":null,"abstract":"<p>A progressive decline in cognitive function occurs as a result of aging and Alzheimer's disease (AD) and is primarily associated with diminished cholinergic neurotransmission. However, the precise mechanisms contributing to cholinergic dysfunction are not fully elucidated. Herein, we evaluated the cholinergic system in wild type (WT) mice and AD-model (<i>App</i>^{<i>NL-G-F</i>}) mice exhibiting overproduction of amyloid-beta 42 (Aβ₄₂). In superfusion experiments, [³H]acetylcholine (ACh) release from the frontal cortex and hippocampal segments preloaded with [³H]choline exhibited no significant differences between adult (6–8 months old) and aged (12–17 months old) WT mice. Uptake of [³H]choline via the high-affinity choline transporter 1 (CHT1) and the subsequent formation/storage of [³H]ACh showed a moderate tendency to decrease associated with aging. In contrast, in <i>App</i>^{<i>NL-G-F</i>} mice, [³H]ACh release was significantly reduced in both the adult and aged groups, with reductions closely related to impaired CHT1 activity and diminished ACh synthesis/storage at cholinergic terminals. Presynaptic cholinergic feedback mechanisms regulating ACh release, as well as the density and subtype distribution of muscarinic ACh receptors, were minimally affected by both aging and Aβ₄₂ overproduction. These results support the Aβ hypothesis, suggesting that presynaptic cholinergic dysfunction arises early and is specifically caused by decreased CHT1 function in the AD forebrain, independent of age-dependent degeneration.\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 5","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.70081","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143938784","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":"EXPRESSION OF CONCERN: Combined Pharmacological, Mutational and Cell Biology Approaches Indicate That p53-Dependent Caspase 3 Activation Triggered by Cellular Prion Is Dependent on Its Endocytosis","authors":"","doi":"10.1111/jnc.70074","DOIUrl":"https://doi.org/10.1111/jnc.70074","url":null,"abstract":"<p><b>EXPRESSION OF CONCERN</b>: C. Sunyach and F. Checler, “Combined Pharmacological, Mutational and Cell Biology Approaches Indicate that p53-Dependent Caspase 3 Activation Triggered by Cellular Prion is Dependent on its Endocytosis,” <i>Journal of Neurochemistry</i> 92, no. 6 (2005): 1399–1407, https://doi.org/10.1111/j.1471-4159.2004.02989.x.</p><p>This Expression of Concern is for the above article, published online on 25 February 2005 in Wiley Online Library (wileyonlinelibrary.com), and has been issued by agreement between the journal Editor-in-Chief, Andrew Lawrence; the International Society for Neurochemistry; and John Wiley &amp; Sons Ltd. A third party reported concerns that a portion of the tubulin control in Figure 2a had been manipulated. Additional investigation by the publisher found evidence that the tubulin bands in Figure 4b had been duplicated in Figure 5a. Author F. Checler responded to an inquiry by the publisher and stated that the concerns were unfounded but also stated that the original data were no longer available due to the time that has elapsed since publication and the departure of co-author C. Sunyach from research. The editors have determined that the evidence of image manipulation and duplication casts doubt on the results presented in the article, and that the veracity of the data presented cannot be confirmed due to the lack of original data. Therefore, the journal has decided to issue an Expression of Concern to inform and alert readers. Author F. Checler disagrees with the retraction. Author C. Sunyach could not be reached for comment regarding the Expression of Concern.</p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 5","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.70074","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143919607","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":"Abstracts for the Latin American Glia Club Workshop: Paving the Way for Glial Cells Function","authors":"","doi":"10.1111/jnc.70056","DOIUrl":"https://doi.org/10.1111/jnc.70056","url":null,"abstract":"","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 5","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143909196","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":"PKG-Mediated Phosphorylation of TOP2A Activates HDAC to Drive Photoreceptor Cell Death in rd1 Mouse Inherited Retinal Degeneration","authors":"Yujie Dong,&nbsp;Wandong Zuo,&nbsp;Yan Li,&nbsp;Xiaoxiao Feng,&nbsp;Chunming Guo,&nbsp;Maorong Chen,&nbsp;Jie Yan,&nbsp;Chunjiang Hou,&nbsp;Hua Peng,&nbsp;Zhulin Hu,&nbsp;Hai Liu,&nbsp;François Paquet-Durand,&nbsp;Kangwei Jiao","doi":"10.1111/jnc.70077","DOIUrl":"https://doi.org/10.1111/jnc.70077","url":null,"abstract":"<div>\u0000 \u0000 <p>Inherited retinal degeneration (IRD) is a debilitating condition characterized by progressive loss of photoreceptor cells. However, the underlying mechanisms remain largely unclear. This study investigated the role of DNA topoisomerase II alpha (TOP2A) and its interplay with protein kinase G (PKG) and histone deacetylase (HDAC) in the <i>rd1</i> mouse model for IRD. Immunofluorescence and quantitative western blotting analyses were performed to evaluate the expression of TOP2A, PKG1, PKG2, HDAC1, and other related markers. TSC24 and suberoylanilide hydroxamic acid were used to specifically inhibit TOP2A and HDAC, respectively, in organotypic retinal explant cultures derived from wild-type or <i>rd1</i> mice. Furthermore, we examined the effect of PKG activity on TOP2A phosphorylation using KT5823. Significant upregulation of TOP2A was observed in the <i>rd1</i> mouse retina compared with wild-type controls, especially in the outer nuclear layer. Phosphorylation levels of TOP2A strongly correlated with photoreceptor cell death. Treatment with TSC24 significantly reduced TOP2A-positive and TUNEL-positive cells. TOP2A phosphorylation was accompanied by HDAC activation, which was mitigated by TSC24. PKG inhibition by KT5823 reduced TOP2A phosphorylation at specific residues and photoreceptor HDAC activity. Our findings position TOP2A in the PKG-TOP2A-HDAC photoreceptor degenerative pathway, offering new potential therapeutic targets for combating IRD-type diseases.\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 5","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143905221","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":"Glutathione Metabolism of the Brain—The Role of Astrocytes","authors":"Ralf Dringen,&nbsp;Christian Arend","doi":"10.1111/jnc.70073","DOIUrl":"https://doi.org/10.1111/jnc.70073","url":null,"abstract":"<p>Astrocytes have essential functions in the brain as partners of neurons in many metabolic and homeostatic processes. The metabolism of the tripeptide GSH (γ-L-glutamyl-L-cysteinyl-glycine) is an important example of a metabolic interaction between astrocytes and neurons. GSH is present in brain cells in millimolar concentrations and has essential functions as an antioxidant and as a substrate for detoxification reactions. A high GSH content protects astrocytes against oxidative stress and toxins and is therefore beneficial for the astrocytic self-defense that helps to maintain the essential functions of astrocytes in the brain and will enable astrocytes to eliminate potential toxins before they may reach other brain cells. In addition, astrocytes provide neurons with the amino acids required for GSH synthesis in a process that involves the export of GSH from astrocytes by the multidrug resistance protein 1, the extracellular processing of GSH via the astrocytic γ-glutamyl transpeptidase to generate the dipeptide cysteinyl-glycine, and the extracellular cleavage of this dipeptide by the neuronal ectopeptidase aminopeptidase N. As GSH export from astrocytes strongly depends on the cytosolic GSH concentration, a high astrocytic GSH content will also facilitate GSH release and thereby the supply of GSH precursors to neighboring neurons. In this article, we will give an overview of the current knowledge on the GSH metabolism of astrocytes, address how a high astrocytic GSH content can help to maintain brain functions, and discuss open questions and future perspectives of research on the functions of astrocytes in the GSH metabolism of the healthy and diseased brain.\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 5","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.70073","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143896909","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":"The Power Struggle: Kynurenine Pathway Enzyme Knockouts and Brain Mitochondrial Respiration","authors":"László Juhász,&nbsp;Krisztina Spisák,&nbsp;Boglárka Zsuzsa Szolnoki,&nbsp;Anna Nászai,&nbsp;Ágnes Szabó,&nbsp;Attila Rutai,&nbsp;Szabolcs Péter Tallósy,&nbsp;Andrea Szabó,&nbsp;József Toldi,&nbsp;Masaru Tanaka,&nbsp;Keiko Takeda,&nbsp;Kinuyo Ozaki,&nbsp;Hiromi Inoue,&nbsp;Sayo Yamamoto,&nbsp;Etsuro Ono,&nbsp;Mihály Boros,&nbsp;József Kaszaki,&nbsp;László Vécsei","doi":"10.1111/jnc.70075","DOIUrl":"https://doi.org/10.1111/jnc.70075","url":null,"abstract":"<p>Numerous illnesses, including neurological and mental disorders, have been associated with mitochondrial dysfunction. Disruptions in mitochondrial respiration and energy production have been linked to dysmetabolism of the tryptophan (Trp)-kynurenine (KYN) pathway, which produces a diverse array of bioactive metabolites. Kynurenic acid (KYNA) is a putative neuroprotectant. The exact mechanisms through which Trp-KYN metabolic dysregulation affects mitochondrial function remain largely unclear. This study investigates the impact of the genetic deletion of kynurenine aminotransferase (KAT) enzymes, which are responsible for KYNA synthesis, on mitochondrial function, specifically mitochondrial respiration and ATP synthesis, and its potential role in neuropsychiatric pathology. CRISPR/Cas9-induced knockout mouse strains kat1^−/−, kat2^−/−, and kat3^−/− were generated. Eight-to-ten-week-old male mice were used, and cerebral and hepatic respiration, complex I- and II-linked oxidative phosphorylation (CI and CII OXPHOS), and complex IV (CIV) activity were measured using high-resolution respirometry. Mitochondrial membrane potential changes were measured with Fluorescence-Sensor Blue and safranin dye. KAT knockout mice exhibited significantly lower cerebellar respiration (CI OXPHOS, CII OXPHOS, and CIV activity) compared to wild-type mice. Lower baseline respiration and attenuated OXPHOS activities were observed in the hippocampus and striatum, particularly in kat2^−/− and kat3^−/− mice. Non-neuronal tissues showed reduced CIV activity, while ADP-stimulated CI and CII OXPHOS remained unchanged. The deletion of the KAT genes significantly impairs mitochondrial respiration and ATP synthesis, potentially contributing to pathogenesis. This study highlights the importance of KYNA in mitochondrial function, offering new insights into potential therapeutic targets for various disorders. Targeting the KYN pathway could mitigate mitochondrial dysfunction in a variety of diseased conditions.\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 5","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.70075","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143901037","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":"IgD-CD38-B Cell Partially Mediates the Protective Effect of Higher Serum Triacylglycerol (53:4) Levels Against Parkinson's Disease","authors":"Yajun Jing,&nbsp;Honglin Zhu,&nbsp;Peisen Yao,&nbsp;Yiming Chen,&nbsp;Xuemiao Lai,&nbsp;Qiu He,&nbsp;Lianghong Yu,&nbsp;Yuanxiang Lin,&nbsp;Dezhi Kang","doi":"10.1111/jnc.70067","DOIUrl":"https://doi.org/10.1111/jnc.70067","url":null,"abstract":"<div>\u0000 \u0000 <p>Emerging evidence suggests that dysregulated lipid metabolism contributes to Parkinson's disease (PD) risk, with chronic inflammation in the central nervous system (CNS) also playing a pivotal role. Although correlations between inflammatory responses, serum lipid metabolism, and PD risk are established, a causal relationship remains unclear. Building on previous findings linking higher serum triacylglycerol (51:4) levels to reduced PD risk, this study explores the potential causal associations between 38 triacylglycerol isoforms and PD risk using Mendelian randomization (MR). We utilized summary-level data from genome-wide association studies (GWAS) on PD, circulating immune cells, inflammatory proteins, and serum lipidomes—including 38 triacylglycerol isoforms, 15 sterol ester isoforms, and 46 phosphatidylcholine isoforms—to assess the relationship between serum lipid profiles and PD. Our analysis revealed that higher levels of serum triacylglycerol (51:4) and triacylglycerol (53:4) were associated with a reduced PD risk, whereas lower levels of phosphatidylcholine (17:0_18:1) and sterol ester (27:1/20:2) were linked to higher PD risk. Notably, multivariable MR analysis confirmed a robust causal association between increased serum triacylglycerol (53:4) and a 24% reduction in PD risk (1 SD higher triacylglycerol (53:4) leading to a 24% [95% CI, 0.54–0.97] risk reduction, <i>p</i> = 0.005). Mediation analysis suggested that circulating immune cells, rather than inflammatory proteins, may mediate the relationship between triacylglycerol (53:4) levels and PD risk. These findings establish a causal link between triacylglycerol (53:4) and PD risk, highlighting the potential role of immune modulation in PD pathogenesis.\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 5","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143888923","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":"Milestone Review: Unlocking the Proteomics of Glycine Receptor Complexes","authors":"Sean D. Fraser,&nbsp;Remco V. Klaassen,&nbsp;Carmen Villmann,&nbsp;August B. Smit,&nbsp;Robert J. Harvey","doi":"10.1111/jnc.70061","DOIUrl":"https://doi.org/10.1111/jnc.70061","url":null,"abstract":"<p>Glycine receptors (GlyRs) are typically known for mediating inhibitory synaptic transmission within the spinal cord and brainstem, but they also have key roles in embryonic brain development, learning/memory, inflammatory pain sensitization, and rhythmic breathing. GlyR dysfunction has been implicated in multiple neurological disease states, including startle disease (GlyR α1β) and neurodevelopmental disorders (NDDs) including autism spectrum disorder (ASD), intellectual disability (ID), developmental delay (DD) and epilepsy (GlyR α2). However, GlyRs do not operate in isolation but depend upon stable and transient protein–protein interactions (PPIs) that influence synaptic localization, homeostasis, signaling pathways, and receptor function. Despite the affinity purification of GlyRs using the antagonist strychnine over four decades ago, we still have much to learn about native GlyR stoichiometry and accessory proteins. In contrast to other neurotransmitter receptors, &lt; 20 potential GlyR interactors have been identified to date. These include some well-known proteins that are vital to inhibitory synapse function, such as the postsynaptic scaffolding protein gephyrin and the RhoGEF collybistin. However, the majority of known interactors either bind to the GlyR α1 and β subunits, or the binding partner in the GlyR complex is unknown. Several potential GlyR interactors are not found at inhibitory synapses and/or have no clear functional role. Moreover, other GlyR interactors are <i>secondary interactors</i> that bind indirectly, for example, via gephyrin. In this review, we provide a critical evaluation of known GlyR interacting proteins and methodological limitations to date. We also provide a road map for the use of innovative and emerging interaction proteomic techniques that will unlock the GlyR interactome. With the emergence of disease-associated missense mutations in the α1, α2 and β subunit intracellular domains in startle disease and NDDs, understanding the identity and roles of GlyR accessory proteins is vital in understanding GlyR function and dysfunction in health and disease.\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 4","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.70061","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143875655","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}