Journal Of Neurochemistry[JOURNAL]
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200 papers
Correction to "Targeting Glutamate Excitotoxicity with Memantine Modulates Glial Response and Protects Motoneurons After Spinal Root Lesion".
J Neurochem · 2026 May · PMID 42051105 · Publisher ↗
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Cerebrospinal Fluid sCD27 as a Biomarker of Neuroinflammatory Disease: A Systematic Review and Meta-Analysis.
Savino ND, Hansen MB, Christiansen AML … +3 more , El Mahdaoui S, Sellebjerg F, Christensen JR
J Neurochem · 2026 May · PMID 42048087 · Full text
Neuroinflammatory diseases of the central nervous system (CNS) present considerable diagnostic challenges due to overlapping clinical features and the lack of specific biomarkers capable of reliably detecting CNS inflamm...
Neuroinflammatory diseases of the central nervous system (CNS) present considerable diagnostic challenges due to overlapping clinical features and the lack of specific biomarkers capable of reliably detecting CNS inflammation. Soluble CD27 (sCD27) is a marker of adaptive immune activation, released upon CD27-CD70 interaction. sCD27 has emerged as a promising cerebrospinal fluid (CSF) biomarker, but its clinical utility remains unclear. This systematic review and meta-analysis aimed to clarify the diagnostic value of CSF sCD27 across neuroinflammatory conditions. We systematically searched PubMed, Embase, and Scopus for studies reporting CSF sCD27 levels in neuroinflammatory disorders versus controls, including demyelinating diseases, autoimmune encephalitis, neuroinfectious diseases, and primary CNS lymphoma, following PRISMA 2020 guidelines. Nineteen studies met the inclusion criteria for qualitative synthesis, and ten provided sufficient quantitative data for meta-analysis, encompassing 685 neuroinflammatory and 751 control participants. Using multivariate and random-effects models, we found significantly elevated levels of CSF sCD27 in neuroinflammatory diseases compared to controls (standardized mean difference [SMD] = 1.24, 95% CI 0.98-1.51, p < 0.0001), with consistent results in sensitivity and subgroup analysis restricted to multiple sclerosis. Despite between-study heterogeneity, largely driven by variation in assay methods, reporting units, and study populations, effect sizes remained large and robust. Most studies also reported excellent diagnostic accuracy, with area under the curve (AUC) values above 0.85, supporting the discriminatory potential of CSF sCD27 for neuroinflammatory diseases versus controls. Collectively, these findings strongly support that CSF sCD27 is a robust biomarker of adaptive immune-mediated neuroinflammation across a spectrum of neuroinflammatory diseases. Future research should focus on assay standardization and consistent reporting practices using well-characterized prospective cohorts of a broader spectrum of neuroinflammatory disorders to define clinical thresholds and facilitate the integration of CSF sCD27 into diagnostic protocols. This study provides a comprehensive synthesis and substantiates CSF sCD27 as a promising biomarker for detecting adaptive immune-mediated neuroinflammation in clinical practice.
Adenosine A Receptors Control the Mis-Localization of Aquaporin-4 in Rats Subject to Repeated Restraint Stress.
Dias L, Ferreira SG, Nabais AM … +3 more , Silva J, Cunha RA, Agostinho P
J Neurochem · 2026 Apr · PMID 42043306 · Full text
Repeated stress triggers anxiety accompanied by a deregulation of cortical glucocorticoid receptors, which is relieved by blocking adenosine A receptors (AR). AR also controls the glymphatic system and the polarization o...
Repeated stress triggers anxiety accompanied by a deregulation of cortical glucocorticoid receptors, which is relieved by blocking adenosine A receptors (AR). AR also controls the glymphatic system and the polarization of its key driver aquaporin-4 (AQP4). Since the glymphatic system is altered upon repeated stress, we now tested if AR blockade could alleviate AQP4 polarization in rats subject to repeated restraint stress (RRS). As expected, RRS enhanced anxiety in the elevated plus maze, decreased self-care behavior in the splash test, and decreased cortical glucocorticoid receptors levels; these alterations were prevented by daily treatment with the selective AR antagonist KW-6002 (3 mg/kg/day). KW-6002 treatment also prevented the RRS-induced decrease of AQP4 density in gliosomes, corresponding to astrocytic membrane endfeet, the perivascular AQP4 polarization in astrocytes, and both perivascular and cellular AQP4 coverage. These findings show that AR controls AQP4 polarization upon restraint stress and prompt considering that AR might control the impact of repeated stress on brain dysfunction through a control of the glymphatic system.
Neonatal Overnutrition Induces Long-Lasting Hypothalamic POMC Silencing and Shapes Distinct Obesity Phenotypes According to Adult Dietary Environments.
Fernández PR, Gaydou L, Schumacher R … +6 more , Rossetti MF, García AP, Morandi GG, Ramos JG, Stoker C, Canesini G
J Neurochem · 2026 Apr · PMID 42028909 · Publisher ↗
Our study aimed to analyze the individual effects of early-life overnutrition (focusing on its long-lasting impact) and adult cafeteria diet (CAF) exposure, as well as their combined effect, on hypothalamic food-intake r...
Our study aimed to analyze the individual effects of early-life overnutrition (focusing on its long-lasting impact) and adult cafeteria diet (CAF) exposure, as well as their combined effect, on hypothalamic food-intake regulation. Neonatal overfeeding was induced by a small litter model (SL, 4 pups/dam), and the control group was raised in normal litters (NL, 10 pups/dam). Male rats received control diet (CON) until postnatal day (PND) 90 and then CON or CAF for 11 weeks. Body weight, naso-anal length and food intake were recorded weekly. At PND167, rats were euthanized to obtain brain, blood and fat pads. Arcuate Nucleus (ARC) was isolated by micropunch technique for qPCR analysis. Hypothalamic gene expression and DNA methylation were analyzed. Neonatal overfeeding and/or adult CAF diet exposure drive obesity development, hyperinsulinemia and altered Homeostatic Model Assessment (HOMA-IR). CAF promotes caloric and nutritional efficiency increase, regardless of the situation in early-life. SL-CAF rats exhibited impaired feeding behavior characterized by a higher standard chow consumption over the palatable foods. At transcriptional level, early overnutrition was associated with lasting reduced Pro-opiomelanocortin (Pomc) expression in ARC, potentially linked to promoter and enhancer hypermethylation. On the other hand, Neuropeptide Y (Npy) expression is decreased by neonatal overnutrition, apparently responding to peripheral stimuli. Leptin receptor expression is reduced by the CAF diet, suggesting a mechanism of leptin resistance. Our research reveals distinct obesity phenotypes, each with specific molecular, epigenetic, and behavioral characteristics. These findings highlight the need for tailored therapeutic strategies that account for these mechanistic differences. Importantly, early-life overnutrition alters hypothalamic regulatory circuits with lasting effects. Together, our findings show how nutritional experiences across the lifespan shape hypothalamic neurochemistry, advancing our understanding of feeding-brain interactions in obesity.
Kinetic Modeling of a Novel Putative Sphingosine-1-Phosphate Receptor 1 (S1PR1) Radiotracer [F]TZ82112 in Nonhuman Primates.
Nai YH, Qiu L, Jiang H … +9 more , Chen H, Snyder AZ, Lee JJ, Wong DF, Huang T, Gropler R, Benzinger TLS, Perlmutter JS, Tu Z
J Neurochem · 2026 Apr · PMID 42027121 · Full text
Sphingosine-1-phosphate receptors (S1PRs) play an important regulatory role in various biological processes, including immune responses and neurodegeneration. We report the binding specificity of an S1PR1 PET radiotracer...
Sphingosine-1-phosphate receptors (S1PRs) play an important regulatory role in various biological processes, including immune responses and neurodegeneration. We report the binding specificity of an S1PR1 PET radiotracer, [F]TZ82112, via in vitro autoradiography blocking studies with S1PR1 modulators in human and rat brain tissues and evaluate the tracer kinetics via kinetic modeling in nonhuman primates (NHPs) to assess its potential for clinical translation. A total of 12 scans were performed in four male macaques (M 1-4). Each macaque had 1-4 baseline scans and at least one blocking scan in three macaques. Arterial input function (AIF) was obtained from M2 and M3 under baseline conditions and M3 after pretreatment with cold TZ82112. The metabolite-corrected plasma AIF was applied to several kinetic models-one-tissue compartment (1TC) and 2TC, and Graphical Logan Analysis. Five candidate reference regions, namely the whole cerebellum, brain stem, occipital cortex, corpus callosum, and cerebral white matter, were investigated for deriving the standardized uptake value ratios (SUVr). The 2TC with four parameters (2TC4K) with blood volume (V) fitting is the most suitable kinetic model for evaluating [F]TZ82112 kinetics. Pretreatment with unlabeled TZ82112 reduced uptake of [F]TZ82112, demonstrating specific binding in all analyzed regions, including potential reference regions. Reduced tracer uptake in in vitro blocking studies further confirmed the tracer specificity to S1PR1. We concluded that accurate [F]TZ82112 quantification requires AIF measurements, owing to the lack of a suitable reference region; no reference region modeling approach or SUVr would be appropriate. Fast tracer uptake and high V values, particularly in the prefrontal cortex and striatum, indicated that [F]TZ82112 enters the brain quickly and has high S1PR1-specific binding in NHP brain. The current findings further support [F]TZ82112 as a good PET radiotracer for the quantification of S1PR1 in the brain, provided an AIF is employed.
Validation of TRPA1 and TRPV1 Antibodies for Expression Detection in Mammalian Cells and Tissues.
de Las Casas M, Hernández-Ortego P, Torres-Montero R … +4 more , De la Peña E, Gomis A, Viana F, Fernández-Trillo J
J Neurochem · 2026 Apr · PMID 42017335 · Full text
Antibodies are key reagents in cell biology and biochemistry research. The validation of their performance, in terms of sensitivity and specificity, is essential for their correct application. TRPV1 and TRPA1 are non-sel...
Antibodies are key reagents in cell biology and biochemistry research. The validation of their performance, in terms of sensitivity and specificity, is essential for their correct application. TRPV1 and TRPA1 are non-selective cation channels expressed in primary sensory neurons, where they mediate the detection of diverse physical and chemical stimuli. They play key roles in nociception and inflammatory processes, making them important targets for mechanistic and therapeutic pain studies, highlighting the need for reliable evaluation of their expression. The detection and quantification of TRPV1 and TRPA1 protein expression is commonly carried out using antibody-based techniques, such as immunohistochemistry and western blotting. However, as with other TRP channels and membrane proteins, antibody performance is frequently suboptimal, leading to potential misinterpretation of results and erroneous conclusions. In this study, we systematically evaluated the performance of five TRPV1 and seven TRPA1 commercial antibodies in immunocytochemistry, immunohistochemistry, and western blotting, using both heterologous and native expression systems. We identified two TRPV1 antibodies that consistently yielded robust and specific signals across all techniques and expression models tested; their specificity was validated using a TRPV1 KO mouse. For the remaining antibodies, we provide guidance to facilitate the selection of the most appropriate reagent according to the experimental approach.
Contextualizing Blood-Based Biomarkers for Dementia Globally.
Duran-Aniotz C, Pizarro M, Migeot J … +4 more , Salazar-Londoño S, Santamaría-García H, O'Bryant SE, Ibanez A
J Neurochem · 2026 Apr · PMID 42003482 · Full text
Blood-based biomarkers (BBMs) are transforming the diagnostic landscape of Alzheimer's disease by enabling scalable, less invasive, and potentially earlier biological characterization. However, most evidence supporting t...
Blood-based biomarkers (BBMs) are transforming the diagnostic landscape of Alzheimer's disease by enabling scalable, less invasive, and potentially earlier biological characterization. However, most evidence supporting their performance, interpretation, and clinical integration derives from highly selected cohorts in high-income settings, raising concerns about external validity, threshold transportability, and equitable implementation across diverse populations. In this Opinion, we argue that advancing BBMs from analytical validity to real-world use requires a shift from biomarker-centric accuracy toward context-aware interpretation frameworks that explicitly account for social, environmental, and health system determinants. Using the amyloid, tau, and neurodegeneration (AT(N)) system as a conceptual anchor, we discuss how BBMs should be positioned according to clearly defined contexts of use, including triage, diagnostic support, prognosis, and clinical trial readiness, rather than treated as universal diagnostic substitutes. We examine how social determinants of health, life-course exposures, and the cumulative exposome interact with comorbidity burden, systemic physiological stress, and health system readiness to shape biomarker distributions, trajectories, and clinical meaning. Evidence from Latin America and other underrepresented settings illustrates how cardiometabolic, vascular, and inflammatory load can modify baseline biomarker levels, challenging the uncritical transfer of cutoffs, reference ranges, and predictive models developed in high-income settings. We conclude that BBMs hold substantial potential to expand access to biological characterization of Alzheimer's disease, but their responsible adoption depends on aligning biological signals with clinical context, social and environmental conditions, and system capacity. Without this alignment, large-scale deployment risks misclassification, inequitable access to care, biased trial enrollment, and distorted estimates of disease burden.
Antisense Oligonucleotides in Parkinson's Disease: Challenges, Opportunities, and the Promise of Low-Intensity Focused Ultrasound for Brain Delivery.
Obika S, Blesa J
J Neurochem · 2026 Apr · PMID 42003475 · Publisher ↗
Parkinson's disease (PD) is a neurodegenerative disorder characterized by dopaminergic neuronal loss in the basal ganglia, for which no disease modifying therapy is currently available. Antisense oligonucleotides (ASOs)...
Parkinson's disease (PD) is a neurodegenerative disorder characterized by dopaminergic neuronal loss in the basal ganglia, for which no disease modifying therapy is currently available. Antisense oligonucleotides (ASOs) have emerged as promising therapeutic candidates, and numbers of preclinical studies with PD models have demonstrated their potential to inhibit α-synuclein aggregation. However, a major obstacle to clinical application of ASOs in neurodegenerative diseases is their limited permeability across the blood-brain barrier. Consequently, currently approved ASOs for neurological disorders are administered intrathecally, which makes it difficult to achieve efficient drug delivery to deep brain structures such as the basal ganglia. Focused ultrasound (FUS)-induced blood-brain barrier opening has attracted interest as a noninvasive strategy to enhance central nervous system drug delivery. Clinical studies have demonstrated that FUS-mediated blood-brain barrier opening can be performed safely in patients with PD and effective delivery of therapeutic agents, such as glucocerebrosidase. Yet, evidence for effective delivery of ASOs to the brain via FUS-induced blood-brain barrier opening is still lacking. This review summarizes current studies of ASOs in PD, together with recent advances in FUS-mediated blood-brain barrier opening. We highlight remaining biological and translational limitations and outline future perspectives for optimizing ASOs delivery with FUS-mediated blood-brain barrier opening to accelerate disease-modifying therapy for PD.
A Comprehensive Characterization of the Phospholipid and Cholesterol Composition of the Uncinate Fasciculus in the Human Brain: Evidence of Age-Related Alterations.
Perlman K, Chen CT, Smith ME … +4 more , Kim J, Turecki G, Bazinet RP, Mechawar N
J Neurochem · 2026 Apr · PMID 42003427 · Full text
The uncinate fasciculus (UF) is a long-range association fiber tract connecting the anterior temporal lobe with the orbitofrontal cortex and has been linked to a multitude of physiological and pathophysiological conditio...
The uncinate fasciculus (UF) is a long-range association fiber tract connecting the anterior temporal lobe with the orbitofrontal cortex and has been linked to a multitude of physiological and pathophysiological conditions such as aging, epilepsy, and the vulnerability to psychopathology posed by a history of childhood abuse (CA). Since the myelin sheath is highly enriched in lipids, changes in white matter (WM) microstructure observed via neuroimaging may reflect alterations in the myelin lipid profile. Given that the UF does not exist in rodents, its molecular properties are highly understudied. Therefore, we sought to quantify the phospholipid FA and cholesterol quantities of the human postmortem UF and evaluate any lipid-related or myelin-constituent gene/protein changes associated with age and history of CA. UF samples were analyzed from individuals with depression who died by suicide with (DS-CA) or without (DS) severe CA, and control individuals (CTRL), with an age span of 15 to 85 years. Phospholipids were separated by thin-layer chromatography; FAs and nonderivatized cholesterol were quantified by gas chromatography-flame ionization detection. The relative expression of myelin-constituent genes and proteins was measured by RT-qPCR and immunoblotting, respectively. We found no robust relationships between CA or depression and lipid measures or myelin-constituent gene/protein levels. In contrast, phospholipids showed pronounced age effects that differed by fraction, with an overall trend of monounsaturated FAs increasing and long-chain omega-6 polyunsaturated FAs decreasing with age. The expression of most myelin-constituent genes and proteins declined with age; PLP1 and MAG showed significant decreases. Therefore, changes in lipid composition and lipid-protein interactions likely contribute to age-related myelin deficits and may in part underlie age-associated cognitive decline.
Schwann Cells in Development, Regeneration, and Therapeutic Applications: Insights From the Sciatic Nerve Model.
Usach V, Soto PA, Setton-Avruj CP
J Neurochem · 2026 Apr · PMID 41992840 · Publisher ↗
The sciatic nerve is the largest nerve in the human body and is frequently affected by lesions, causing pain and even loss of sensitivity. The sciatic nerve injury model provides a robust platform to study the degenerati...
The sciatic nerve is the largest nerve in the human body and is frequently affected by lesions, causing pain and even loss of sensitivity. The sciatic nerve injury model provides a robust platform to study the degeneration-regeneration process. In this context, Schwann cells (SC) are central regulators of peripheral nervous system (PNS) development, homeostasis, and regeneration. During development, SC arise from neural crest-derived precursors and undergo tightly regulated lineage progression, culminating in myelinating and non-myelinating phenotypes. This process is orchestrated by coordinated transcriptional, signaling, and epigenetic mechanisms that control radial sorting, differentiation, and myelination. Following nerve injury, SC exhibit remarkable plasticity, reprogramming into a specialized repair phenotype that promotes axonal regeneration through debris clearance, trophic support, immune modulation, and the formation of Büngner bands. This work aims to summarize the known history of the plasticity and functions of SC during nerve development and regeneration. It also aims to highlight the most recent advances regarding the molecular networks underlying SC plasticity, as well as epigenetic regulators that enable dynamic transitions between cellular states. This work also describes the factors compromising nerve regeneration and functional recovery, and summarizes the emerging therapeutic strategies aimed to overcome these limitations by enhancing SC plasticity, modulating the injury microenvironment, and developing alternative cell sources, including stem cell-derived Schwann-like cells. A deeper understanding of SC heterogeneity, lineage dynamics, and regenerative mechanisms will be essential for advancing translational strategies. Collectively, this review underscores the pivotal role of SC in nerve regeneration and highlights innovative approaches to harness their therapeutic potential.
Peri-Microvascular Glycogen and Lactate Regulate Capillary Constrictions and Ischemia Outcome in Mice.
Uruk G, Donmez-Demir B, Yilmaz-Ozcan S … +10 more , Cakir-Aktas C, Taskiran-Sag A, Gurler G, Duran J, Guinovart JJ, Baba O, Morita T, Karatas H, Dalkara T, Yemisci M
J Neurochem · 2026 Apr · PMID 41989058 · Full text
Ischemic stroke results in sudden blood flow cessation, thus unmet energy requirements. Glycogen stored around peri-microvascular astrocyte end-feet may mediate capillary contractility and cerebral blood flow alterations...
Ischemic stroke results in sudden blood flow cessation, thus unmet energy requirements. Glycogen stored around peri-microvascular astrocyte end-feet may mediate capillary contractility and cerebral blood flow alterations. Under glucose-deprived and hypoxic conditions, lactate derived from these glycogen stores may serve as an emergency fuel to sustain tissue perfusion during an acute period of ischemic stroke. To elucidate the impact of glycogen utilization on brain microcirculation, both 1,4-dideoxy-1,4-imino-d-arabinitol hydrochloride (DAB) administered to wild-type (WT) intracerebroventricularly (i.c.v.), and central nervous system and astrocyte-specific glycogen synthase-1 knock-out (GYS1 and GYS1) mice were used. We assessed regional cerebral blood flow changes in vivo, pericyte-associated microvascular constrictions, semi-quantitative peri-microvascular glycogen levels, and lactate transporters ex vivo. Experiments revealed that both pharmacological and genetic manipulations of glycogen metabolism also resulted in severely compromised blood flow dynamics and higher infarct volumes after stroke. Disrupted cerebral glycogen utilization induced CD13-positive pericyte-associated microvascular constrictions, which were highly correlated with peri-microvascular periodic acid Schiff (PAS), IV58B6, and ESG1A9 intensity levels. Lastly, intravenous (i.v.) D/L-lactate and i.c.v. L-lactate administration reversed microvascular constrictions while glycogen phosphorylase inhibition potently reduced microvascular monocarboxylate transporter-1 (MCT1) coverage. In conclusion, disrupted glycogen utilization causes ischemic-like microvascular constrictions, increases susceptibility to brain ischemia, and is reversible with systemic lactate administration. Understanding the role of glycogen and lactate metabolism at the neurogliovascular level in the brain may provide novel insight into the pathophysiology and therapeutic opportunities of cerebrovascular disorders.
E3 Ubiquitin Ligase Nedd4-2 Exacerbates Seizure-Induced Mitochondrial Defects in an Alzheimer's Disease Mouse Model.
Wang Y, Zhu J, Lizarazo S … +6 more , Lee KY, Wong O, Azim S, Yook Y, Kumar V, Tsai NP
J Neurochem · 2026 Apr · PMID 41981995 · Full text
Seizure is one of the common comorbidities in Alzheimer's disease (AD). Seizures in AD have been shown to occur more often with early-onset disease, particularly when there is a familial presenilin I (PS1) mutation or ab...
Seizure is one of the common comorbidities in Alzheimer's disease (AD). Seizures in AD have been shown to occur more often with early-onset disease, particularly when there is a familial presenilin I (PS1) mutation or abnormal expression of amyloid precursor protein (APP). AD patients with seizures have been associated with a faster decline in cognitive functions. However, it remains unclear how seizures exacerbate neurodegeneration in AD. Here, we showed that, using a kainic acid-induced acute seizure model, mitochondrial function is enhanced and the reactive oxygen species (ROS) are reduced in the brain of wild-type (WT) mice but not in an AD mouse model, APP/PS1 mice. These data suggest a lack of protective mechanism following seizures in APP/PS1 mice. Mechanistically, we found that an E3 ubiquitin ligase, the neural precursor cell-expressed developmentally downregulated protein 4-like (Nedd4-2), is elevated but stays dephosphorylated in APP/PS1 mice upon seizure inductions. Immunocytochemistry and sub-cellular fractionation experiments demonstrate an interaction between Nedd4-2 and mitochondria. Unbiased proteomics analysis suggests that Nedd4-2 regulates the expression of multiple mitochondrial proteins including one of the key mitochondrial outer membrane proteins, Mitofusin 2 (MFN2). Upon seizure induction, Nedd4-2 exhibits elevated interaction with mitochondria and downregulates MFN2 in APP/PS1 mice but not in WT mice. These data suggest that seizures aggravate mitochondrial dysfunction in AD, and Nedd4-2, which acts as a negative mitochondrial regulator, contributes to this effect. Altogether, our findings illustrate a potential mechanism by which seizures exacerbate neurodegeneration in AD and suggest Nedd4-2 as a novel therapeutic target for AD patients with comorbid seizures.
Simultaneous Expression of Sigma-1 Receptor and Tetraspanins Highlights Pathways of Receptor Sorting Into Extracellular Vesicles.
Vavers E, Kopanchuk S, Veiksina S … +5 more , Jonane J, Mathur C, Nasirova N, Midekessa G, Rinken A
J Neurochem · 2026 Apr · PMID 41981990 · Publisher ↗
Sigma-1 receptor (Sig1R) is an endoplasmic reticulum (ER) chaperone protein involved in regulating ER function, cellular stress responses, and autophagy, and disturbed Sig1R function has been associated with neurodegener...
Sigma-1 receptor (Sig1R) is an endoplasmic reticulum (ER) chaperone protein involved in regulating ER function, cellular stress responses, and autophagy, and disturbed Sig1R function has been associated with neurodegenerative and neuropsychiatric disorders, including Alzheimer's disease and amyotrophic lateral sclerosis. Although Sig1R has been implicated in secretory pathways and detected extracellularly, its direct presence in isolated extracellular vesicles (EVs) has not been clearly established. In this study, we aimed to confirm Sig1R in isolated EVs by co-expressing it alongside tetraspanin EV markers. Expression of fluorescently tagged Sig1R together with fluorescent protein-labeled tetraspanins CD9, CD63, and CD81 in both cells and isolated EVs was verified using live-cell imaging, emission spectrum measurements, and Western blotting. Efficient expression of these proteins in cells was achieved by using the MultiBacMam expression system and their presence in EVs was detected through advanced TIRF-based multi-well single-particle EV analysis. We observed significantly higher levels of Sig1R in CD63- and CD9-labeled EVs in comparison with CD81-labeled EVs. The obtained data suggest that Sig1R may be released into the extracellular space via exocytotic pathways linked to exosome secretion. The presence of Sig1R in exosomes underscores its potential as a biomarker in neurological disorders, emphasizing the need for further exploration of its diagnostic and other applications.
The Role of Loss-of-Function KCNH2 Variants in Cardiac Arrhythmias, Seizures and the Risk of Sudden Unexpected Death in Epilepsy.
Lee HM, Gan XN, Aung KP … +3 more , Forster IC, Reid CA, Soh MS
J Neurochem · 2026 Apr · PMID 41981942 · Full text
Sudden Unexpected Death in Epilepsy (SUDEP) is the leading cause of mortality in patients in epilepsy, yet its underlying mechanisms are poorly understood. Emerging evidence suggests a significant role for genetic factor...
Sudden Unexpected Death in Epilepsy (SUDEP) is the leading cause of mortality in patients in epilepsy, yet its underlying mechanisms are poorly understood. Emerging evidence suggests a significant role for genetic factors that influence cardiac function in SUDEP risk, particularly loss-of-function variants in KCNH2, which encodes the K11.1 potassium channel. K11.1 channels are expressed in both cardiac and neuronal tissues. Pathogenic KCNH2 variants are strongly associated with cardiac arrhythmias leading to increased risk of sudden cardiac death. There is also evidence that KCNH2 variants can influence seizure susceptibility. Furthermore, K11.1 is expressed in brain autonomic and cardiorespiratory centres, where its impairment may compromise autonomic function, including breathing. Therefore, changes in K11.1 channel function in both central and cardiac tissues could potentially contribute to increased SUDEP risk. In this review, we explore the potential dual contribution of K11.1 channel dysfunction to SUDEP risk. We hypothesise how this dual-system vulnerability may predispose individuals with pathogenic KCNH2 variants to both cardiac arrest and respiratory failure following seizures. By integrating genetic, electrophysiological, and neuroanatomical evidence to support our hypothesis, this review presents a multidisciplinary framework for understanding SUDEP and highlights the potential of pathogenic KCNH2 variants as a biomarker for risk and targeted intervention.
When Pathways Converge: Iron, Lipid Peroxidation, and α-Synuclein in Ferroptosis-Driven Dopaminergic Neurodegeneration.
Sperlich CL, Stockwell BR, Farina M
J Neurochem · 2026 Apr · PMID 41968973 · Full text
The selective degeneration of dopaminergic neurons is a hallmark of Parkinson's disease and related disorders. While multiple cell death pathways have been implicated, ferroptosis has recently emerged as a critical mecha...
The selective degeneration of dopaminergic neurons is a hallmark of Parkinson's disease and related disorders. While multiple cell death pathways have been implicated, ferroptosis has recently emerged as a critical mechanism. This iron-dependent form of regulated cell death is driven by the accumulation of phospholipid hydroperoxides, leading to oxidative membrane damage. Dopaminergic neurons are intrinsically vulnerable to ferroptosis due to their high iron content, active dopamine metabolism (a source of reactive oxygen species), and relatively low antioxidant defenses. Here we synthesize evidence linking ferroptosis to dopaminergic neurodegeneration in Parkinson's disease and related conditions, detailing the molecular mechanisms involving iron dyshomeostasis, lipid peroxidation, and α-synuclein pathology. We further evaluate growing preclinical data demonstrating that pharmacological inhibition of ferroptosis is neuroprotective and discuss the clinical implications, therapeutic potential, and ongoing challenges of translating these findings into effective treatments for patients.
Early Effects of Poly(I:C)-induced Neuroinflammation on Hippocampal Astrocyte Function and Glycolytic Metabolism.
Vizuete AFK, Garcez JPM, Pellenz MCM … +5 more , de Lima JA, Taday J, Souza JM, Leite MC, Gonçalves CA
J Neurochem · 2026 Apr · PMID 41968971 · Publisher ↗
Concern is growing about the role of neurotropic viruses, such as Zika virus, West Nile virus, herpes simplex virus, SARS-CoV-2, and human immunodeficiency virus, in central nervous system (CNS) infections, which trigger...
Concern is growing about the role of neurotropic viruses, such as Zika virus, West Nile virus, herpes simplex virus, SARS-CoV-2, and human immunodeficiency virus, in central nervous system (CNS) infections, which trigger host immune responses, neuronal dysfunction and brain injury. Astrocytes function as immune system cells and, together with microglia, participate in the activation and maintenance of neuroinflammatory responses, a common pathophysiological event in neurodegenerative diseases. The reactive phenotype of glial cells leads to the synthesis and release of inflammatory mediators inducing a neurometabolic shift to nonoxidative glycolysis, a phenomenon similar to the Warburg effect. However, since viruses require energy from host cells to replicate, it is essential to understand the increase in glucose consumption during viral infections. For this purpose, we used an early polyinosinic:polycytidylic acid [Poly(I:C)] induced neuroinflammation model to investigate its effects on astrocyte function and neurometabolic responses in two approaches: acute hippocampal slices and in vivo intraperitoneal administration from male Wistar rats (PN30). We evaluated the effects of a dose-response curve of Poly(I:C), an immunostimulant agent that mimics double-stranded RNA virus infection, on the neuroinflammatory response, astrocyte reactivity, and glycolytic parameters. Poly(I:C) induced neuroinflammation and astrocyte reactivity in a dose-dependent manner. Both models of Poly(I:C)-induced early neuroinflammation and astrocyte reactivity which leads to neurometabolic reprogramming with enhanced several glycolytic parameters, such as glucose uptake and hexokinase activity, methylglyoxal (MG) synthesis and affect the glyoxalase-1 (GLO1) activity. Accordingly, inflammatory and glycolytic inhibitors reduced the glycolytic parameters induced by Poly(I:C). As expected, the inflammatory inhibitors downmodulated neuroinflammatory parameters, with arundic acid in particular reversing astrocyte reactivity. Moreover, the downregulation of the glycolytic pathway had a greater effect on the pronounced inflammatory process, and reversed the astrocyte reactivity induced by Poly(I:C) neuroinflammation. Our data are consistent with the hypothesis that a metabolic shift is required to maintain neuroinflammatory signaling, particularly in early Poly(I:C) induced neroinflammation, and highlight the glycolytic pathway as a potential target for controlling the neuroinflammatory response.
Correction to "Astrocyte Bioenergetic Remodeling as a Central Trait of Disrupted Glucocorticoid Signaling: Mechanisms and Implications for Stress Vulnerability".
J Neurochem · 2026 Apr · PMID 41960610 · Publisher ↗
Abstract loading — click title to view on PubMed.
ATG14-Mediated SNARE Complex Activation Promotes ΔFosB Degradation to Ameliorate Levodopa-Induced Dyskinesia.
Wu Y, Liu K, Zhang Z … +7 more , Ma Z, Tang Z, Chang A, Ouyang H, Zhai H, Cao X, Xu Y
J Neurochem · 2026 Apr · PMID 41954056 · Full text
The chronic accumulation of ΔFosB in striatal medium spiny neurons has been implicated as a pivotal contributor to the pathogenesis of levodopa-induced dyskinesia (LID). While recent studies have implicated autophagy in...
The chronic accumulation of ΔFosB in striatal medium spiny neurons has been implicated as a pivotal contributor to the pathogenesis of levodopa-induced dyskinesia (LID). While recent studies have implicated autophagy in the degradation of ΔFosB and the amelioration of LID, the precise mechanisms remain elusive. We induced LID in a unilateral 6-hydroxydopamine-lesioned parkinsonism rat model via chronic levodopa treatment. To modulate the autophagy pathway, we overexpressed ATG14 in the striatum of LID rats and administered chloroquine, an autophagy inhibitor, peripherally. We assessed LID severity using abnormal involuntary movements (AIMs) scores. Western blotting, real-time quantitative polymerase chain reaction, immunofluorescence, immunohistochemistry, transmission electron microscopy, and Golgi staining were employed to measure autophagy flux, synaptic alterations, and ΔFosB levels. Chronic levodopa treatment reduced ATG14 and SNARE complex (STX17, SNAP29, and VAMP8) levels, disrupted their interaction, impaired autophagy flux, affected synaptic function, and led to ΔFosB accumulation in the striatum of PD rats. Upregulating ATG14 in the striatum of LID rats improved AIMs scores, facilitated SNARE-mediated autophagosome-lysosome fusion, restored synaptic deficits, and promoted ΔFosB degradation. However, these beneficial effects of ATG14 upregulation were negated by chloroquine administration. Our findings suggest that upregulating ATG14 enhances SNARE formation, promoting autophagy flux and thereby reducing LID occurrence by facilitating ΔFosB degradation.
Targeting Glutamate Excitotoxicity With Memantine Modulates Glial Response and Protects Motoneurons After Spinal Root Lesion.
Leão AVM, Bíscaro GG, de Oliveira ALR … +1 more , Cartarozzi LP
J Neurochem · 2026 Apr · PMID 41949382 · Full text
Spinal root injuries trigger longitudinal spinal cord damage, leading to motoneuron degeneration, gliosis, and synaptic loss. Glutamate excitotoxicity through NMDA and AMPA receptor overstimulation is a key driver of thi...
Spinal root injuries trigger longitudinal spinal cord damage, leading to motoneuron degeneration, gliosis, and synaptic loss. Glutamate excitotoxicity through NMDA and AMPA receptor overstimulation is a key driver of this pathology, highlighting NMDA receptor antagonists as potential neuroprotective agents. Here, we evaluated the effects of memantine after unilateral L4-L6 ventral root crush (VRC) in adult C57BL/6JUnib mice. Animals received daily oral gavage of vehicle or memantine (30, 45, or 60 mg/kg) for 14 days. At 28 days post-injury, histological analysis showed that memantine reduced astrogliosis and microglial activation, while enhancing motoneuron survival (most pronounced at 45 mg/kg, p < 0.001) and preserving synaptic coverage (p < 0.01), without significant changes in VGLUT-1 or GAD65 expression. Consistently, RT-qPCR analysis revealed early upregulation of inflammatory markers (Ccr2, Itgam) in vehicle-treated mice, which was attenuated by memantine at 3-7 days post-injury (p < 0.05). These findings indicate that memantine confers neuroprotection in VRC by modulating inflammatory gene expression, mitigating gliosis, and promoting motoneuron survival, supporting its therapeutic potential in spinal cord injuries.
Clinical Evaluation of Three KRS Families and Cellular Analysis of Distinct ATP13A2 Mutations Reveal Different Levels of Iron Accumulation.
Erterek E, Temizci B, Tekgül Ş … +5 more , Çakır B, Başak AN, Gültekin M, Yapıcı Z, Karabay A
J Neurochem · 2026 Apr · PMID 41944191 · Full text
Kufor-Rakeb Syndrome (KRS) is a rare neurodegenerative disease caused by homozygous mutations in the ATP13A2 gene. The ATP13A2 protein, found in lysosomal and late-endosomal membranes, performs cellular functions such as...
Kufor-Rakeb Syndrome (KRS) is a rare neurodegenerative disease caused by homozygous mutations in the ATP13A2 gene. The ATP13A2 protein, found in lysosomal and late-endosomal membranes, performs cellular functions such as iron-chelating agent transport and intracellular iron homeostasis. Mutations in ATP13A2 can lead to intracellular iron accumulation; however, whether KRS caused by an ATP13A2 mutation falls under Neurodegeneration with Brain Iron Accumulation disorders has long been debated. The most fundamental reason is that magnetic resonance imaging (MRI) cannot identify iron deposits in the basal ganglia in all KRS cases. We hypothesize that analyzing iron deposition at the cellular level could be more sensitive in detecting varying levels of iron accumulation associated with different ATP13A2 mutations, and it may be more useful when conventional MRI fails to detect iron, yields inconclusive results, or cannot be performed. We identified two new ATP13A2 mutations (p.Leu518_Thr519del, and p.Leu939Pro) in this study and comparatively investigated the impacts of three distinct ATP13A2 mutations (p.Pro474fs, p.Leu518_Thr519del, and p.Leu939Pro) using KRS patients' primary fibroblasts and MCF7 cells overexpressing these mutated ATP13A2 proteins to analyze if these different mutations of ATP13A2 can cause differing levels of iron accumulation. Following the detection of iron deposits via Prussian blue staining and inductively coupled plasma mass spectrometry, the cell viability was assessed via MTT assay to ascertain the impact of iron accumulation. Each type of ATP13A2 mutation led to iron accumulation; however, frameshift and deletion mutations resulted in more iron accumulation than the missense mutation. In addition, the transient overexpression of the wild-type ATP13A2 attenuated the cell death caused by iron accumulation. This study demonstrated that different types of ATP13A2 mutations are related to varying levels of iron accumulation and provided an explanation for the inconsistent perspectives on the association of KRS with iron accumulation.
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