Journal Of Neurochemistry[JOURNAL]
Sun
200 papers
Septins in the Middle-Makers and Breakers of Membrane Contact Sites.
Holt TJ, Spiliotis ET
J Neurochem · 2026 Jun · PMID 42283483 · Full text
Intracellular communication in neurons requires precise coordination of signals across geometrically complex and highly compartmentalized cellular architectures. Membrane contact sites (MCS)-specialized junctions where t...
Intracellular communication in neurons requires precise coordination of signals across geometrically complex and highly compartmentalized cellular architectures. Membrane contact sites (MCS)-specialized junctions where two organelles are closely apposed without undergoing fusion-have emerged as key organizational hubs enabling efficient exchange of ions, lipids, and metabolites, yet the cytoskeletal proteins that organize and regulate these junctions remain poorly understood. Here, we review evidence that septins-a conserved family of heteromeric GTP-binding proteins that assemble into filamentous oligomers and polymers-function as integral components of MCS in neurons and beyond. Septins associate with hyperboloid, hourglass-shaped membrane curvatures and distinct membrane domains and organelles through polybasic motifs, amphipathic helices, and transmembrane domains. We review how septins establish diffusion barriers at endoplasmic reticulum (ER)-plasma membrane (PM) contacts in budding yeast and consider evidence that analogous mechanisms operate at dendritic branch points and spine necks in mammalian neurons. We examine septin roles in regulating store-operated calcium entry at ER-PM contacts and explore how septins regulate membrane contacts at presynaptic active zones. Additionally, we highlight how septins organize membrane contacts between host organelles and intracellular pathogens, scaffolding autophagic, mitochondrial, and lysosomal membranes for bacterial clearance. Collectively, these findings support the view that septins constitute a versatile and underappreciated class of MCS tethers whose paralog- and isoform-specific complex compositions may confer spatial and functional selectivity for distinct MCS, opening new avenues for understanding organelle connectivity in health and disease.
Targeting Brain Cholesterol Homeostasis in Alzheimer's Disease: Mechanisms and Therapeutic Perspectives.
Ruthirakuhan M, Taha AY, Swardfager W
J Neurochem · 2026 Jun · PMID 42283223 · Full text
Cholesterol is a fundamental component of the central nervous system, supporting myelin integrity, synaptic structure, membrane organization, and neuronal signaling. Because the brain is largely isolated from peripheral...
Cholesterol is a fundamental component of the central nervous system, supporting myelin integrity, synaptic structure, membrane organization, and neuronal signaling. Because the brain is largely isolated from peripheral cholesterol pools, tight regulation of brain cholesterol homeostasis is required to sustain neuronal and glial function across the lifespan. Growing evidence indicates that disruption of this balance is not merely a downstream consequence of neurodegeneration, but an upstream contributor to Alzheimer's disease (AD) pathogenesis. Altered brain cholesterol homeostasis has been linked to amyloidogenic processing, tau pathology, neuroinflammation, synaptic dysfunction, and cerebrovascular injury. This review synthesizes current evidence showing how multiple converging stressors, including peripheral hypercholesterolemia, neurodegeneration, oxidative stress, and inflammatory signaling, perturb brain cholesterol regulation. These drivers disrupt the coordinated processes of cholesterol synthesis, metabolism, and transport, shifting the system from tightly regulated sterol flux toward impaired clearance, abnormal lipid distribution, and membrane instability. Such disturbances remodel membrane lipid composition, alter lipid raft organization, and impair glial-neuronal lipid coupling, thereby accelerating amyloid-β production, tau-related vulnerability, innate immune activation, and neurovascular dysfunction. Finally, we provide an overview of therapeutic strategies aimed at restoring cholesterol balance, and highlight the potential of integrated, multi-target strategies to complement amyloid- and tau-directed therapies. By clarifying how disruptions in brain cholesterol homeostasis link systemic and central stressors to AD pathology, this review identifies cholesterol regulation as a critical, upstream axis for therapeutic intervention and disease prevention.
Effects of Lysine Deacetylation Inhibition Alone or in Combination With Arimoclomol on TDP-43 Proteinopathy.
Scozzari S, Columbro SF, Favagrossa M … +8 more , Tortarolo M, Cagnotto A, Salmona M, De Marco G, Bendotti C, Calvo A, Pasetto L, Bonetto V
J Neurochem · 2026 Jun · PMID 42283221 · Full text
Cytoplasmic inclusions containing TAR DNA-binding protein 43 kDa (TDP-43) are recognized as a major pathological feature of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. Peptidyl-prolyl cis-trans isome...
Cytoplasmic inclusions containing TAR DNA-binding protein 43 kDa (TDP-43) are recognized as a major pathological feature of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. Peptidyl-prolyl cis-trans isomerase A (PPIA) interacts with TDP-43 and influences its aggregation and function. This interaction is facilitated by PPIA Lys-acetylation. Here, we investigated whether restoring lysine acetylation homeostasis exerts protective effects on TDP-43 proteinopathy in vitro and in vivo and how this relates with PPIA. We found that vorinostat/SAHA, a broad-spectrum histone deacetylase (HDAC) inhibitor that increases PPIA acetylation, is able to reverse TDP-43 mislocalization in a cellular model of TDP-43 proteinopathy. We confirmed its effects in peripheral blood mononuclear cells from ALS patients and explored its impact on TDP-43 proteinopathy and PPIA acetylation in the Thy1-hTDP-43 mouse model. Thy1-hTDP-43 mice treated with SAHA showed a delayed onset of TDP-43 pathology, associated with PPIA nucleus-cytoplasm redistribution, lower neurodegeneration and neuroinflammation, and improved neuromuscular function markers. However, these effects were transient. When combined with arimoclomol, a heat shock protein co-inducer, a mitigation of the neurodegeneration was sustained. A synergistic effect was observed in periphery, greatly enhancing tubulin acetylation and reducing phosphorylated TDP-43 accumulation in the sciatic nerve and acetylcholine receptor γ-subunit expression in gastrocnemius muscle. This study suggests that HDAC inhibition could be beneficial in restoring TDP-43 localization and function through multiple mechanisms, including modulation of PPIA acetylation. The combination of lysine deacetylation inhibition and arimoclomol shows a synergistic effect in vivo and has potential as a therapeutic approach for patients.
A Biological Framework for Parkinson's Disease: Advances in α-Synuclein-Centered Biomarkers and Staging.
Hatano T, Lin CH, Cardoso F
J Neurochem · 2026 Jun · PMID 42261981 · Publisher ↗
Parkinson's disease (PD) is a neurodegenerative disorder marked by substantial heterogeneity in pathological distribution, disease trajectories, and coexisting neuropathologies. Despite this biological complexity, curren...
Parkinson's disease (PD) is a neurodegenerative disorder marked by substantial heterogeneity in pathological distribution, disease trajectories, and coexisting neuropathologies. Despite this biological complexity, current diagnosis and staging of PD remain largely anchored in clinical manifestations. Neuronal aggregation of misfolded α-synuclein and degeneration of the nigrostriatal dopaminergic system precede the onset of motor symptoms; this phase is termed the prodromal stage of PD. Therefore, clinically based frameworks inherently limit early detection and stratification. In contrast, Alzheimer's disease has undergone a paradigm shift toward a biomarker-driven biological definition, prompting a similar reappraisal of PD as a biologically defined disease continuum. Accumulating evidence indicates that pathological α-synuclein aggregates in PD extend beyond the central nervous system and exhibit heterogeneous patterns of initiation and propagation. Methodological advances have expanded the capacity to detect these pathological species in vivo. In particular, α-synuclein seed amplification assays (SAA) enable the detection of seeding-competent α-synuclein species in biofluids and peripheral tissues, providing evidence consistent with α-synuclein pathology; however, SAA should not be interpreted as a direct reflection of disease stage, progression, or pathological burden. Furthermore, the development of α-synuclein positron emission tomography ligands offers the prospect of non-invasive visualization of pathological burden, spatial distribution, and longitudinal target engagement, thereby complementing biofluid-based approaches. Together, these biomarker advances underpin emerging biologically anchored classification and staging frameworks, such as the SynNeurGe system and the Neuronal α-Synuclein Disease Integrated Staging System (NSD-ISS). These frameworks integrate α-synuclein pathology, neurodegeneration, genetic background, and clinical features to define disease identity and progression across asymptomatic, prodromal, and manifest stages. We synthesize recent advances in α-synuclein-centered biomarkers and biological staging frameworks and discuss how their convergence is beginning to reshape PD from a primarily symptom-based diagnosis toward a molecularly grounded disease continuum. This transition has the potential to complement clinically defined PD with biologically informed perspectives.
Targeting Neuroinflammation in Depression: The Integrative Role of Sigma-1 Receptor Modulation.
Wang JY, Yang DY, Li YF … +1 more , Ren P
J Neurochem · 2026 Jun · PMID 42261810 · Publisher ↗
Depression is a leading cause of global disability, yet remains insufficiently treated by conventional monoaminergic antidepressants, which are limited by their delayed onset, variable efficacy, and significant side effe...
Depression is a leading cause of global disability, yet remains insufficiently treated by conventional monoaminergic antidepressants, which are limited by their delayed onset, variable efficacy, and significant side effects. Accumulating evidence positions neuroinflammation, driven by glial dysfunction, peripheral-central immune crosstalk, and associated cellular stress pathways as a pivotal upstream mechanism in the pathogenesis of depression, contributing to both neurotransmitter dysregulation and impaired synaptic plasticity. This review examines the integrative role of the Sigma-1 receptor (Sig-1R), a ligand-operated chaperone predominantly localized at the mitochondria-associated endoplasmic reticulum membrane (MAM), as a promising therapeutic target for mitigating this neuroinflammatory cascade. We systematically synthesize preclinical evidence demonstrating that pharmacological activation of Sig-1R produces broad anti-neuroinflammatory effects, including the promotion of microglial homeostasis and a shift toward an anti-inflammatory phenotype, attenuation of reactive astrogliosis, suppression of key pro-inflammatory signaling hubs such as NF-κB and the NLRP3 inflammasome, and mitigation of oligodendrocyte dysfunction. Beyond immunomodulation, Sig-1R activation alleviates endoplasmic reticulum stress, enhances autophagic and mitophagic clearance, supports mitochondrial bioenergetics, and strengthens endogenous antioxidant defenses. Together, these actions disrupt the vicious cycle linking cellular stress, inflammation, and synaptic impairment. We also evaluate advances in representative Sig-1R agonists and review available clinical trial data, including results on the novel multi-target agent AXS-05. Genetic and pharmacological loss-of-function studies further emphasize the essential role of Sig-1R in mood regulation and stress resilience. In summary, the Sigma-1 receptor serves as a key regulator of cellular homeostasis and adaptation. Its agonists represent a promising therapeutic strategy that moves beyond symptomatic monoaminergic modulation to mechanistically target the core inflammatory and proteostatic disturbances in depression, offering the potential for improved treatment efficacy.
Enhancing Dopamine Accumulation in Secretory Vesicles of PC12 Cells: Mechanisms, Applications and Limitations.
Socas-Pérez N, Borges R, Machado JD
J Neurochem · 2026 Jun · PMID 42244191 · Full text
Fifty years ago, Green and Tischler established the chromaffin-derived cell line PC12. This line has been extremely successful to explore many biological functions as PC12 are easily manipulated by molecular biology tech...
Fifty years ago, Green and Tischler established the chromaffin-derived cell line PC12. This line has been extremely successful to explore many biological functions as PC12 are easily manipulated by molecular biology techniques. These cells retain many features from the original source, although enzymes from the catecholamine synthetic pathway exhibit a very low expression or directly have disappeared. This is crucial when PC12 are required to explore the secretory responses, especially when electrochemical techniques are required. In this review we focus on the main characteristics of PC12 cells compared with chromaffin cells, with particular emphasis on the properties of large dense-core vesicles and their secretory mechanisms and how different culture maneuvers can enhance the secretory performance of PC12 cells by increasing dopamine synthesis and storage.
Calcium Buffering in Astrocytes and Its Relevance for Experimental Data Interpretation and Computational Modeling.
Lenk K, Zeug A, Müller FE
J Neurochem · 2026 Jun · PMID 42244178 · Full text
Astrocytic Ca signaling is essential for maintaining physiological brain function, including the modulation of synaptic transmission, neurovascular coupling, and ion homeostasis. However, the spatiotemporal dynamics of a...
Astrocytic Ca signaling is essential for maintaining physiological brain function, including the modulation of synaptic transmission, neurovascular coupling, and ion homeostasis. However, the spatiotemporal dynamics of astrocytic Ca activity are highly sensitive to Ca buffering, which shapes the amplitude, duration, and spread of cytosolic and organellar signals. These buffers include endogenous components such as cytosolic Ca binding proteins, as well as organelles like the endoplasmic reticulum acting as Ca stores. Additionally, exogenous buffers are introduced in experiments, including chelators, synthetic dyes, and genetically encoded Ca indicators. Both types of buffers can profoundly alter experimental observations, making it challenging to accurately interpret Ca dynamics. Computational modeling offers a powerful approach to separate these effects, enabling systematic exploration of how the buffering capacity of specific system components influences astrocytic intracellular and intercellular signaling. By incorporating experimental data with realistic biophysical buffering parameters, models can make predictions that are difficult to achieve empirically and help identify key parameters that shape astrocytic Ca physiology. In this review, we discuss how buffering components influence astrocyte Ca activity and their integration into modeling predictions. Future advances in computational modeling, combined with extensive experimental data, will be crucial for enhancing our understanding of astrocytic Ca regulation and elucidating its role in health and disease.
Brain Bioenergetics in Aging: Neurovascular and Neurometabolic Coupling and Fuels: 15th International Conference on Brain Energy Metabolism.
Drew KL, Zorec R, Vardjan N … +2 more , Kreft M, McKenna MC
J Neurochem · 2026 Jun · PMID 42244173 · Full text
This Preface introduces the Special Issue entitled, "Brain Bioenergetics in Aging: Neurovascular and Neurometabolic Coupling and Fuels," which is comprised of manuscripts contributed by invited speakers and program/organ...
This Preface introduces the Special Issue entitled, "Brain Bioenergetics in Aging: Neurovascular and Neurometabolic Coupling and Fuels," which is comprised of manuscripts contributed by invited speakers and program/organizing committee members who participated in the 15th International Conference on Brain Energy Metabolism (ICBEM) held on September 17-21, 2024, in Ljubljana, Slovenia. The conference covered the latest developments in research related to (i) coordination of neurometabolic and neurovascular coupling and homeostasis of energy metabolism in healthy aging and Alzheimer's disease, (ii) in vivo imaging modalities for study of neurometabolic and neurovascular coupling, (iii) mitochondrial and metabolic alterations and resilience in injured and aging brain, (iv) astrocyte metabolism in Alzheimer's and other neurodegenerative diseases, (v) microglial support of neuronal metabolism and role in neurodegeneration, (vi) neuronal mitochondria and disease, (vii) lipids and transporters in brain function, metabolism and Alzheimer's disease, and (viii) metabolic regulation of cognition. The special issue contains 19 manuscripts on these topics.
Energy Stress-Induced Neuroprotection Against Ferroptosis in Dopaminergic Neurons.
Jonneaux A, Laine W, Maboudou P … +6 more , Kluza J, Bonte MA, Gouel F, Devos D, Marchetti P, Devedjian JC
J Neurochem · 2026 Jun · PMID 42223207 · Publisher ↗
Ferroptosis, an iron-dependent form of regulated necrosis, is implicated in the pathogenesis of Parkinson's disease (PD). We studied the influence of energy stress on ferroptosis in differentiated dopaminergic neurons (L...
Ferroptosis, an iron-dependent form of regulated necrosis, is implicated in the pathogenesis of Parkinson's disease (PD). We studied the influence of energy stress on ferroptosis in differentiated dopaminergic neurons (LUHMES). Glucose deprivation conferred protection against ferroptosis induced by erastin or arachidonic acid plus iron by reducing lipid peroxidation. Glucose withdrawal did not protect against RSL3-induced ferroptosis, suggesting that direct GPX4 inhibition cannot be reversed by metabolic modulation. The expression of ferroptosis markers ACSL4, GPX4, xCT, and TFRc remained unaltered during glucose deprivation. Inhibition of glycolysis using 2-deoxyglucose confirmed the role of energy stress in the regulation of ferroptosis. Activation of AMP-activated protein kinase (AMPK) by AICAR protected LUHMES cells from erastin-induced ferroptosis, even in the presence of glucose. Conversely, AMPK expression inhibition by siRNA re-sensitized cells to ferroptosis under glucose-free conditions. These findings suggest that glucose metabolism and AMPK-mediated energetic stress play crucial roles in regulating ferroptosis in dopaminergic neurons, with potential implications for understanding the mechanisms of neurodegeneration in PD. These findings identify a potential bioenergetic checkpoint regulating ferroptosis susceptibility under conditions of severe energy stress.
Transcranial Direct Current Stimulation Attenuates Ischemic Stroke-Induced Autonomic and Behavioral Dysfunction via a RAS-Autophagy-Iron Axis in the Brainstem.
Hsu Y, Lin CC, Huang CH … +1 more , Chang AYW
J Neurochem · 2026 Jun · PMID 42212720 · Publisher ↗
Ischemic stroke frequently results in sympathetic overactivity and blood pressure dysregulation, primarily due to impaired central autonomic regulation within the rostral ventrolateral medulla (RVLM) in the brainstem. Ho...
Ischemic stroke frequently results in sympathetic overactivity and blood pressure dysregulation, primarily due to impaired central autonomic regulation within the rostral ventrolateral medulla (RVLM) in the brainstem. However, the molecular mechanisms underlying this dysfunction remain insufficiently defined. In this study, we examined the regulatory interplay between the renin-angiotensin system (RAS), autophagy, and iron metabolism in the RVLM in a transient middle cerebral artery occlusion model (MCAO) of ischemic stroke in Sprague-Dawley rats. Our results revealed that stroke induced an imbalance in RAS pressor and depressor signaling, disrupted autophagic flux, and altered iron storage protein expression. These molecular abnormalities were accompanied by elevated blood pressure and suggest a mechanistic link to sympathetic dysregulation. Notably, transcranial direct current stimulation (tDCS) mitigated these stroke-induced abnormalities by downregulating RAS pressor signaling, restoring impaired autophagic activity-including autophagic ferritin degradation-and consequently reducing iron accumulation-associated oxidative stress in the RVLM. Collectively, our findings propose a putative molecular cascade contributing to post-stroke sympathetic overactivity and highlight non-invasive tDCS as a potential neuromodulatory intervention to restore neurochemical homeostasis in the RVLM.
Exercise Increases the Sensitivity of Cerebral Glucose Metabolism to Intranasal Insulin in Young, Healthy Adults.
Carr JMJR, Koep JL, Duffy JS … +11 more , Brewster LM, Bird JD, Monteleone JA, Monaghan TDR, Islam H, Steele AR, Howe CA, Thomas KN, MacLeod DB, Ainslie PN, Gibbons TD
J Neurochem · 2026 Jun · PMID 42205008 · Publisher ↗
Exercise provides a therapeutic pathways to mitigate cognitive decrements through benefits to cerebrovascular and neurological function. Intranasal delivery of insulin also offers a therapeutic pathway, possibly via enha...
Exercise provides a therapeutic pathways to mitigate cognitive decrements through benefits to cerebrovascular and neurological function. Intranasal delivery of insulin also offers a therapeutic pathway, possibly via enhancing cerebral metabolism. We assessed cerebral oxygen and glucose metabolism (CMRO and CMRglc, respectively) via cross-brain blood sampling and ultrasound measurement of cerebral blood flow (CBF), following two successive intranasal insulin (INI) administrations (52 IU); once at rest, and again at rest but following 1 h of prolonged cycling exercise. Measurement timepoints following both INI administration were 5, 10, 15, 20, 30, 45, and 60 min post. Eleven healthy young adults (5 female, 22.4 ± 1.7 kg/m) completed this protocol, and, between INI bouts, completed cycling exercise, consisting of 2-3 one-minute bouts at 80%-100% of work rate max followed by 90 min at 90% of lactate threshold (~2 h total). At rest, INI had no effect on CMRO (p = 0.141) while CMRglc may have been elevated (p = 0.086). Comparing the effects of INI pre- and post-exercise, CMRO was not different (condition, p = 0.333). Collapsing both conditions (pre- and post-exercise) CMRO was increased from baseline at 30 min (time, p = 0.007). CMRglc was also not different between conditions (condition, p = 0.498), but was increased (time, p < 0.001) from baseline (0.34 ± 0.02 mmol/min) to 45 min (0.40 ± 0.02 mmol/min) by 20% ± 28% (p = 0.017) across both conditions. Whole brain cerebral metabolism sensitivity to intranasal insulin is minimal at rest, but seems to be increased following exercise, likely due to exercise induced hypoglycaemia driving a supercompensatory response. These findings provide mechanistic support for the cognitive benefits of exercise, and potentially intranasal insulin, through enhanced cerebral metabolism.
Deep Brain Stimulation of the Nucleus Accumbens Modulates Effort-Based Decision-Making and Phasic Dopamine Release in Male Wistar Rats.
McCullough S, Varela RB, Houghton T … +2 more , Cruickshank H, Tye SJ
J Neurochem · 2026 Jun · PMID 42201781 · Publisher ↗
The initiation and sustained expression of motivated behaviour is strongly regulated by mesolimbic dopamine (DA) release within the nucleus accumbens (NAc). Deep brain stimulation (DBS) has demonstrated efficacy in treat...
The initiation and sustained expression of motivated behaviour is strongly regulated by mesolimbic dopamine (DA) release within the nucleus accumbens (NAc). Deep brain stimulation (DBS) has demonstrated efficacy in treating refractory psychiatric disorders characterised by dysfunctional motivated drive and related behaviours. However, the neurobiological mechanisms underlying DBS effects at the local and circuit levels remain unclear. This study aimed to investigate the effects of NAc DBS on effort-based decision-making and local phasic DA neurotransmission in male Wistar rats. Male Wistar rats (N = 8) were trained on a concurrent fixed ratio 5/chow effort-related choice task (ERCT) until stable baseline performance was reached. On the test day, animals underwent a 2-h session of high-frequency NAc DBS (130 Hz; 90 μs pulse width; 500 μA) immediately prior to behavioural testing, with additional testing conducted on subsequent days to assess prolonged effects. In a separate experiment, the effects of identical NAc DBS parameters (or sham) on ventral tegmental area (VTA)-evoked (120 pulses; 60 Hz; 2 ms pulse width; 200-500 μA) DA release in the NAc core were quantified using fast-scan cyclic voltammetry in urethane-anesthetised rats (N = 12). Acute bilateral NAc DBS transiently reduced overall food-related motivation while maintaining effort-based choice bias. In parallel, NAc DBS significantly suppressed VTA-evoked NAc DA release compared to sham, although a moderate reduction was also observed in sham controls. DA reuptake kinetics remained unchanged across groups. NAc DBS transiently suppresses overall food-related motivation while maintaining effort-based decision-making. Attenuated phasic DA neurotransmission with active DBS may contribute to this behavioural effect.
SARS-CoV-2 Infection Induces Dopaminergic Neuronal Loss in Midbrain Organoids.
Jarazo J, da Silva ES, Glaab E … +2 more , Perez-Bercoff D, Schwamborn JC
J Neurochem · 2026 May · PMID 42178947 · Publisher ↗
COVID-19 is mainly associated with respiratory symptoms, although several reports show that SARS-CoV-2 affects the nervous system. We evaluated the effects of SARS-CoV-2 infection on human derived midbrain organoids by e...
COVID-19 is mainly associated with respiratory symptoms, although several reports show that SARS-CoV-2 affects the nervous system. We evaluated the effects of SARS-CoV-2 infection on human derived midbrain organoids by exposing them to the virus (multiplicity of infection 0.05, 16-h exposure) and analyzing cellular and molecular changes at 4 and 28 days post-infection using immunofluorescence microscopy and RNA sequencing. SARS-CoV-2 nucleocapsid protein preferentially colocalized with tyrosine hydroxylase-positive (TH+) dopaminergic neurons, inducing neurite fragmentation and cellular stress. Transcriptomic analysis revealed dysregulation of pathways related to cell stress and death, DNA damage response, neurodevelopment, and neuronal survival at both timepoints. Persistent alterations in vesicle trafficking, Notch signaling, and mitochondrial function were observed at 28 days post-infection. Analysis of non-coding RNA expression highlighted dysregulated genomic regions associated with viral replication and neurite growth. These findings demonstrate selective vulnerability of dopaminergic neurons to SARS-CoV-2 infection with persistent molecular alterations, providing mechanistic insights into potential neurological consequences of COVID-19.
SUMOylation In Cerebral Ischaemia: A Dynamic, Isoform-Specific Regulator of Neuroprotection and Injury.
Gissoni JM, Campos KF, Vieira HLA … +3 more , Netto CA, Durán-Carabali LE, Cimarosti HI
J Neurochem · 2026 May · PMID 42175537 · Publisher ↗
Hypoxia-ischaemia and reperfusion (HI/R) damage is a result stemming from any event that interrupts the brain's blood supply, such as the occlusion of a blood vessel. In neurons, the molecular mechanisms involved in the...
Hypoxia-ischaemia and reperfusion (HI/R) damage is a result stemming from any event that interrupts the brain's blood supply, such as the occlusion of a blood vessel. In neurons, the molecular mechanisms involved in the HI/R cascade are diverse in nature, ranging from proteomic, genomic, and transcriptomic alterations in the cells. Many of these changes are governed by post-translational modifications such as SUMOylation, which can quickly and reversibly alter the fate of key proteins. This review summarises current evidence regarding the role of SUMOylation in key molecular pathways in major in vivo and in vitro models of cerebral HI/R. Our review reinforces the concept of SUMOylation being a dynamic and time-dependent process that functions as a rapid molecular switch, affecting major pathways across different cell types and cellular compartments. Moreover, the context-dependent pathological and neuroprotective action of SUMOylation in different pathways involved in HI/R is explored. It sheds light on a novel notion placing aberrant SUMO-1 conjugation as the main culprit in reperfusion damage, whereas SUMO-2/3 principally serves as a compensatory mechanism during ischaemia to prevent damage. Nevertheless, it also highlights important gaps in the current scientific evidence regarding the role of SUMO, underscoring the need for further investigation.
Early Surge in Brain GFAP Distribution in Female Hamsters With Mild Peripheral COVID-19.
Rahmani Manesh M, Wicki-Stordeur LE, York NS … +10 more , Vendramelli R, Warner B, Vecchiarelli HA, Rainier-Pope L, Khakpour M, Larkey CA, Bennouna LR, Tremblay MÈ, Kobasa D, Swayne LA
J Neurochem · 2026 May · PMID 42175525 · Publisher ↗
Mild to moderate respiratory COVID-19 is commonly associated with a range of neurological symptoms. The two primary proposed mechanisms linking this primarily peripheral disease to the brain, include brain entry of perip...
Mild to moderate respiratory COVID-19 is commonly associated with a range of neurological symptoms. The two primary proposed mechanisms linking this primarily peripheral disease to the brain, include brain entry of peripheral circulating cytokines through a compromised blood-brain barrier, and/or direct brain infection. It has been proposed that the resulting neuroinflammation (i.e., inflammation taking place in the brain) could impair synaptic transmission, causing cognitive dysfunction. One key aspect of neuroinflammation is increased astrocyte reactivity, also known as 'astrogliosis'. Astrogliosis is characterized by altered astrocyte morphology, proliferative capacity, gene expression, and function. Direct investigation of astrogliosis in different brain regions in the context of mild to moderate COVID-19 has been limited. To this end, we quantified changes to astrocytes in a Syrian hamster model of mild to moderate respiratory COVID-19 in five regions of interest: cortex, corpus callosum, hippocampus, bordering the third ventricle, and dorsal striatum. We extracted brains at 1-, 3-, 5-, 7-, and 31-days post-inoculation and from uninfected controls, and immunolabeled sections with astrocyte- (GFAP and SOX9) and neuron- (NEUN) specific markers. We captured tiled confocal micrographs of entire brain sections and quantified these markers in the aforementioned brain regions using a newly-developed unbiased analysis pipeline. At 3-days post-inoculation, we identified a significant, transient increase in GFAP distribution in female hamsters in the cortex, as well as non-significant increases in the hippocampus and corpus callosum. We also found increased GFAP-positive process complexity, an indicator of astrocyte complexity, at 3-days post-inoculation in the female cortex. There were no changes in astrocyte (SOX9), neuron (NEUN) or total cell (Hoechst) numbers. Moreover, there were no changes in male hamsters at any time point in any region of interest. Our findings provide the first spatiotemporal insight into sex differences in astrogliosis in the context of COVID-19.
Modulation of Murine Hippocampal Synaptic Plasticity by Microbial Metabolites: Sex-Specific Effects of the Short-Chain Fatty Acid Butyrate.
Collins MK, Rosell-Cardona C, Golubeva AV … +5 more , McDermott MM, Cronin AM, Clarke G, O'Riordan KJ, Cryan JF
J Neurochem · 2026 May · PMID 42163562 · Publisher ↗
The microbiota-gut-brain-axis is a bidirectional communication system between the trillions of microbes in the gastrointestinal tract and the brain. This axis influences brain processes like learning and memory, but the...
The microbiota-gut-brain-axis is a bidirectional communication system between the trillions of microbes in the gastrointestinal tract and the brain. This axis influences brain processes like learning and memory, but the underlying mechanisms aren't fully understood. Microbial metabolites, particularly short-chain fatty acids (SCFAs) from dietary fibre fermentation, are considered key mediators. We investigated the effects of the three most abundant SCFAs, acetate, butyrate, and propionate, on ex vivo hippocampal slice electrophysiology to explore potential sex-specific mechanisms. We used physiologically relevant concentrations to ensure translational relevance. Our findings show that a 40-min exposure to 3 μM butyrate enhanced long-term potentiation (LTP) in both male and female mice. Butyrate's effects were mediated by the free fatty acid receptor 3 (FFAR3), as its inhibition with β-Hydroxybutyrate (BHB) abolished the enhanced potentiation in slices from female mice, but not males. BHB alone had no effect on LTP in either sex. To understand this dimorphism, we examined messenger ribonucleic acid (mRNA) expression of FFARs and SCFA transporters in cornu ammonis 1 (CA1) hippocampal tissue but found no explanatory differences. Acetate and propionate had no significant effect on LTP, basic synaptic efficacy, or short-term plasticity. In conclusion, our study provides novel insights into the sex-specific modulation of hippocampal synaptic plasticity by butyrate. Our data suggest that FFAR3 activation is crucial for these effects in females, highlighting the gut microbiota's potential to shape hippocampal function. Further studies are warranted to investigate the behavioural consequences of enhanced hippocampal butyrate and to fully parse the mechanisms behind the sex differences we observed.
Effects of a Bacterial Multi-Strain Formulation on Locomotor Sensitization and the Gut Microbiota Structure Induced by Repeated Volatilized Cocaine Exposure in Rats.
Fabius S, Urbanavicius J, Fernández-Ciganda S … +4 more , Lozano J, Piccini C, Zunino P, Scorza C
J Neurochem · 2026 May · PMID 42163548 · Publisher ↗
The gut microbiota (GM), the community of microorganisms inhabiting the gastrointestinal tract, has emerged as a relevant factor in the pathogenesis of substance use disorders (SUD). However, more evidence is required to...
The gut microbiota (GM), the community of microorganisms inhabiting the gastrointestinal tract, has emerged as a relevant factor in the pathogenesis of substance use disorders (SUD). However, more evidence is required to advance in this field of research. In previous research we showed that exposure to volatilized cocaine altered GM composition in rats, suggesting that its modulation could attenuate cocaine effects. In this study, we investigated whether GM modulation through a lactobacilli-based multi-strain formulation influenced behavioral and microbiological outcomes in rats repeatedly exposed to volatilized cocaine. Adult male Wistar rats were given the bacterial formulation or vehicle (milk) orally for 28 days. During the last 7 days, animals were exposed to volatilized cocaine, and locomotor sensitization and anxiety-related behaviors were assessed. Fecal microbiota composition, short-chain fatty acids, and plasma cytokine levels were also evaluated. Results showed that cocaine induced locomotor sensitization, which was not significantly attenuated by the bacterial treatment. Interestingly, cocaine-sensitized animals showed a decrease in locomotor activity on days 6 and 7, suggesting a tolerance-like effect, while bacterial treatment tended to prevent it, maintaining an elevated activity. No significant differences were observed in anxiety-related behaviors. Marked GM structural changes, particularly in β-diversity, were detected in animals receiving bacteria and cocaine treatments. Amplicon sequence variants (ASVs) belonging to the genera Limosilactobacillus and Negativibacillus were reduced, whereas ASVs related to the genus Helicobacter and Parasutterella excrementihominis increased in the bacteria/cocaine group compared to control and the other treated groups. Propionic acid levels were reduced only in cocaine-treated rats, while interleukin (IL)-6 and IL-10 plasma concentrations remained unchanged. Although the multi-strain formulation induced behavioral changes alongside modifications in GM structure, accurate strain selection is required to mitigate cocaine-related effects. Furthermore, new studies are needed to elucidate the mechanisms underlying GM-brain interactions in SUD.
Astrocytes as Histaminergic Gatekeepers of Anxiety: A New Pathway for Emotional Control.
Augustine GJ, Verkhratsky A
J Neurochem · 2026 May · PMID 42153574 · Publisher ↗
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Towards Mechanism-Informed Treatments for Mental Health.
Bengoetxea de Tena I, Sallie FN, Rodriguez Abiero A … +25 more , Rizzi B, Champarini LG, Corti E, Masella G, Dunn AL, Binder LB, Wenzel TJ, Robles AI, Anversa RG, Tremblay C, Fokoua AR, de Lima RMS, D'Ávila M, Truong TTT, Pierce JC, Rodrigues RS, Dinamarca-Villarroel L, Almeida FB, Piironen AK, Aguiar AFL, Jaramillo AM, Santos L, de Lange A, Nutt DJ, Lawrence AJ
J Neurochem · 2026 May · PMID 42152538 · Full text
Neuropsychiatric disorders represent a significant global health burden. Despite decades of research, current treatments typically provide only symptomatic relief, rather than addressing the underlying mechanisms of thes...
Neuropsychiatric disorders represent a significant global health burden. Despite decades of research, current treatments typically provide only symptomatic relief, rather than addressing the underlying mechanisms of these conditions. Historically, research focused on the dopaminergic and serotonergic systems, which are deeply involved in the pathophysiology of many mental health disorders, including depression, schizophrenia, anxiety, autism spectrum disorder (ASD), and different substance use disorders, including alcohol use disorder (AUD). However, therapies targeting these systems have limitations, often only producing partial symptom relief plus compliance-limiting side effects. This highlights the need for improved treatments that may emerge from a broader understanding of the neurobiological bases of these conditions, especially neurochemical systems beyond dopamine and serotonin. Additional monoamines (e.g., histamine, acetylcholine, norepinephrine), neurolipid systems (e.g., endocannabinoids), and diverse signaling molecules such as neuropeptides, trace amines, and cytokines are increasingly recognized as key players in the dysfunction of neural circuits. In this review, which originated from the International Society for Neurochemistry (ISN)/Journal of Neurochemistry 5th Flagship School in October 2024 held in Naxos, Greece, we describe the importance of these neuromodulatory systems in the pathophysiology of select neuropsychiatric disorders, discuss their potential as targets for therapeutic intervention, exploring how they may offer more effective, mechanism-based treatments. We also highlight recent clinical trials, underscoring the progress in advancing towards clinical application, as well as sex-specific neurobiological differences, a historically overlooked, yet fundamental determinant of the pathophysiology of neuropsychiatric disorders. We propose that expanding our focus beyond traditional monoamines offers a promising avenue for the development of new, disease-modifying treatments that can more effectively address the underlying causes of neuropsychiatric disorders. By targeting these pathways, we believe it may be possible to develop therapies that restore balance to dysregulated brain circuits and improve long-term outcomes for patients.
The Chromatin-Modifying Protein RCOR2/CoREST2 Safeguards Axon-Dendrite Growth and Microtubule Stability in Brain Neurons.
Wilson C, Rozés-Salvador V, Drube JF … +4 more , Cardozo Gizzi AM, Salguero J, Moyano AL, Cáceres A
J Neurochem · 2026 May · PMID 42152495 · Publisher ↗
Understanding the mechanisms that underlie neuronal dynamics is crucial to promoting brain health. The chromatin-modifying protein RCOR2 (also named CoREST2) has recently gained attention for its neuroprotective roles. A...
Understanding the mechanisms that underlie neuronal dynamics is crucial to promoting brain health. The chromatin-modifying protein RCOR2 (also named CoREST2) has recently gained attention for its neuroprotective roles. Although previous work has firmly established RCOR2's importance in neurogenesis and aging, its contributions to post-mitotic neurons remain understudied. This gap limits our ability to unveil its broader significance for brain health. In this study, we used the rat primary culture of embryonic hippocampal neurons, highly enriched in pyramidal glutamatergic neurons, to show that RCOR2 preserves the structural integrity of axons and dendrites. By combining state-of-the-art imaging techniques, including confocal, AiryScan2, and STED microscopy, we unveiled that RCOR2 is highly packed within neuronal nuclei, where it maintains the spatial organization of heterochromatin. The delivery of shRNA sequences targeting RCOR2, either by transient transfection or lentiviral infection, led to its partial knockdown and a pronounced shortening of axons and dendrites. This phenotype was paralleled by an abnormal accumulation of microtubule-associated proteins (MAPs), including MAP2 and Tau, revealed by qRT-PCR, immunoblotting, and confocal imaging. Strikingly, RCOR2 knockdown neurons show increased axonal MAP2, suggesting the loss of axonal identity. Moreover, z-stack imaging revealed an abnormal increase in the tyrosinated-tubulin/acetylated-tubulin ratio-a molecular marker of microtubule (MT) stability-indicating reduced MT stability. In this regard, the treatment with a nanomolar and MT-stabilizing dose of taxol (3 nM) partially rescued the neuritic growth of RCOR2 knock-down neurons, suggesting a MT-dependent mechanism. These findings unveil neuron-specific functions of RCOR2, highlighting its protective role in sustaining neuronal architecture during early development.
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