Journal Of Neurochemistry[JOURNAL]
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200 papers
CASPR2 Autoimmune Antibodies Induce Neuronal Hyperactivity in Human Brain Organoids.
Oliveira AR, Cammarata G, Seabra C … +13 more , Cardoso AM, Santos HJ, Guedes J, Sequeira D, Santos JMM, Oliveira G, Cardoso AL, Fernandes D, Leite MI, Coutinho E, Carvalho AL, Ferreira L, Peça J
J Neurochem · 2026 Feb · PMID 41725505 · Full text
Gestational transfer of brain-reactive antibodies is a risk factor for neurodevelopmental disorders. Contactin-associated protein-like 2 (CASPR2) is a known target for pathogenic maternal autoantibodies which have been p...
Gestational transfer of brain-reactive antibodies is a risk factor for neurodevelopmental disorders. Contactin-associated protein-like 2 (CASPR2) is a known target for pathogenic maternal autoantibodies which have been proposed to interfere with fetal neurodevelopment. However, the impact of CASPR2 antibodies on human brain development remains largely unknown. Here, to better understand the neurophysiological changes that occur in the presence of these pathogenic autoantibodies, we cultured unguided human neural organoids for a period of 6-months in media containing anti-CASPR2 antibodies. We then performed neurophysiological characterization via whole-cell patch-clamp and calcium imaging in acute organoid slices. Our results reveal that CASPR2 antibody exposure increased spontaneous synaptic activity, enhanced the maximal frequency of action potential firing and of spontaneous network activity. These findings are consistent with a state of neuronal hyperexcitability, a phenotype which is observed in several models of neurodevelopmental disorders. Mechanistically, the alterations observed in action potential waveform are in accordance with a role for CASPR2 in the regulation of voltage-gated potassium channels and a pathological role for CASPR2 autoantibodies in driving neuronal hyperexcitability.
Glia-to-Axon Transfer of Ribosomes and miRNAs: A Novel Paradigm in Neural Repair.
Marín-Venegas F, Court FA
J Neurochem · 2026 Feb · PMID 41714810 · Publisher ↗
Schwann cells communicate with neurons not only through soluble cues but also via intercellular transfer of ribosomes and exosome-mediated delivery of cargo. Recent studies have established that Schwann cell-derived exos...
Schwann cells communicate with neurons not only through soluble cues but also via intercellular transfer of ribosomes and exosome-mediated delivery of cargo. Recent studies have established that Schwann cell-derived exosomes are powerful promoters of nerve repair, capable of enhancing axon regrowth, remyelination, and functional recovery in numerous models. These effects are mediated via multifactorial cargo (miRNAs, mRNAs, proteins) that modulate neurons, glia, endothelial, and immune cells. Importantly, what began as a novel biological insight is now rapidly moving toward therapeutic innovation. Schwann cell-derived exosomes thus represent both a novel mode of glia-neuron communication and a promising avenue for next-generation therapies for nerve regeneration.
Unraveling Network Pharmacology-Based Therapeutics of Anthranilate Sulfonamides via Sirtuins/FOXO3a Cascade in Alzheimer's Disease.
Ruankham W, Prachayasittikul V, Pingaew R … +5 more , Jeungprasopsuk W, Tantimongcolwat T, Prachayasittikul V, Prachayasittikul S, Phopin K
J Neurochem · 2026 Feb · PMID 41714304 · Full text
Sulfonamide-based compounds have been a clinically attractive scaffold for drug development and proven as antioxidant and antimicrobial agents, but their pharmacological derivatives containing anthranilates (SA1-4) and t...
Sulfonamide-based compounds have been a clinically attractive scaffold for drug development and proven as antioxidant and antimicrobial agents, but their pharmacological derivatives containing anthranilates (SA1-4) and therapeutic targets are not clearly clarified. To unravel the neuroprotective roles and underlying mechanisms of SA1-4 against oxidative injury and healthy longevity crosstalk, a combination of in vitro experiments, in silico modeling, and network pharmacology was employed. Pretreatment with SA1-4 in human neuronal SH-SY5Y cells significantly regulated sirtuins (SIRTs)/forkhead box class O 3a (FOXO3a)-mediated longevity signaling pathway via targeting endogenous antioxidant enzymes (i.e., superoxide dismutase 2 [SOD2] and catalase [CAT]), apoptotic cascades (i.e., Bcl-2-associated X-protein [BAX] and B-cell lymphoma-2 [BCL-2]), mitochondrial balance, and ultimately led to the neuronal rescue. Molecular docking simulations support the possibility of the SA1-4 modulatory effect within the active binding site of SIRT1. Importantly, in silico predictions of pharmacokinetic profiles suggested that the synthetic compounds possessed preferable drug-like properties, good oral bioavailability, and safety profiles. Network pharmacology also revealed the involvement of SA1-4 and key targets-regulated SIRTs in neurodegeneration, including non-amyloidogenic cascade, tau phosphorylation, calcium homeostasis, insulin-mediated glucose uptake, and neuroinflammation. Therefore, SA1-4 exert promising multi-target therapeutic strategies against oxidative damage, potentially offering alternative anti-Alzheimer candidates for further clinical neurodegenerative and anti-aging therapeutics.
Sphingolipids in Emotional Well-Being.
Kalinichenko LS, Zoicas I, Mühle C … +2 more , Kornhuber J, Müller CP
J Neurochem · 2026 Feb · PMID 41700345 · Full text
Emotional well-being is a multifactorial concept, which comprises not only life quality of human individuals, but also their mental and physical health. It encompasses several key parameters, many of which have behaviora...
Emotional well-being is a multifactorial concept, which comprises not only life quality of human individuals, but also their mental and physical health. It encompasses several key parameters, many of which have behavioral representation in daily life. These include finding positive meaning of life events, ability to maintain supportive and caring social interactions, reward-oriented behavior, and many others. It is well-known that the behavioral phenotype is tightly bound to certain physiological and metabolic factors, among which sphingolipid (SL) balance of the organism and especially central nervous system might play an important role. Recent research proposes that SLs mediate multiple components of emotional well-being. The most abundant brain SL types, ceramides and gangliosides, dynamically shape the composition of protein carrying cellular membranes and overall neuronal plasticity. Multiple studies show the contribution of SLs to normal brain functioning and corresponding beneficial behavioral phenotypes, such as stress resilience, cognitive performance, and social interactions, which determine emotional well-being. On the other hand, an imbalance in SL metabolism affects normal functioning of cells and thus contributes to the development of several psychiatric disorders, such as depression, anxiety, cognitive decline, schizophrenia, and others. SLs are suggested as a potentially new mechanism of the key behavioral manifestations of emotional well-being, which might be further investigated as new biomarkers of life quality as well as physical and mental resilience.
CTBP1 In Brain Development: A Novel Variant c.107G>C,p.(R36P) Leads to a Distinct Neurodevelopmental Disorder.
Nishijo T, Yanagi K, Ito H … +8 more , Hamada N, Nakamura S, Chinen Y, Fukuhara Y, Iwamoto I, Kaname T, Okamoto N, Nagata KI
J Neurochem · 2026 Feb · PMID 41674141 · Publisher ↗
CTBP1 (C-terminal-binding protein 1) is a multifunctional protein that acts as a transcriptional co-repressor in the nucleus and a regulator of membrane fission in the cytoplasm. Variants in CTBP1 have been associated wi...
CTBP1 (C-terminal-binding protein 1) is a multifunctional protein that acts as a transcriptional co-repressor in the nucleus and a regulator of membrane fission in the cytoplasm. Variants in CTBP1 have been associated with neurodevelopmental disorder termed HADDTS (Hypotonia, ataxia, developmental delay, and tooth enamel defect syndrome; OMIM#617915). However, the pathophysiological mechanism of this genetic disorder remains unclear. Whole exome sequencing was performed on a 20-year-old male patient with severe mental retardation, atrial septal defect, ataxia, and dysmorphic features. The patient was found to have a de novo missense variant, c.107G>C,p.(R36P), within the PLDLS (Pro-Leu-Asp-Leu-Ser) binding cleft of CTBP1. However, the patient did not fulfill the diagnostic criteria for HADDTS. Therefore, the pathophysiological significance of this variant was investigated in vitro and in vivo, comparing it with p.R342W, a recurrent pathogenic variant in HADDTS. Transient expression of the p.R36P and p.R342W variants reduced the number and total length of dendrites in primary cultured hippocampal neurons. In vivo acute expression of them caused a migration delay of excitatory neurons and disrupted both dendritic arborization and spine formation during corticogenesis. Subsequent electrophysiological analyses suggested that these variants reduced excitatory synaptic transmission. Additionally, the p.R36P variant, but not p.R342W, reduced the excitability of layer II/III pyramidal neurons. We also report two new cases with the p.R342W variant that meet the diagnostic criteria for HADDTS. Our results show that CTBP1 plays an essential role in brain development and that the novel variant may cause a new developmental disorder distinct from HADDTS.
Microglia at the Forefront: New Insights From the Glial Club South Cone Meeting 2025.
Giambartolomei GH, Iribarren P, Pasquini LA … +1 more , Peluffo H
J Neurochem · 2026 Feb · PMID 41668347 · Publisher ↗
Microglia are the primary innate immune cells of the central nervous system and act as dynamic regulators of neural development, homeostasis, and response to injury. This review summarizes key discussions from the Glial...
Microglia are the primary innate immune cells of the central nervous system and act as dynamic regulators of neural development, homeostasis, and response to injury. This review summarizes key discussions from the Glial Club South Cone Meeting 2025, focusing on (i) mechanisms and regulation of microglial phagocytosis and its dual role in tissue repair and neurodegeneration, (ii) the emerging immunometabolic and neuroprotective functions of the lipid-sensing receptor CD300f in aging and Alzheimer's disease models, and (iii) the context-dependent roles of autophagy in microglial activation, inflammation control and proteostasis. We highlight how phagocytic signaling (IFN, IL-6, "eat-me," "don't-eat-me" cues), immune receptors and epigenetic regulation shape microglial states and function. Translational implications are discussed, including strategies to preserve beneficial microglial functions while limiting detrimental phagoptotic and pro-inflammatory responses. Identifying receptor-specific ligands, clarifying causal roles of phagocytosis in neurodegeneration, and dissecting autophagy-dependent quality-control pathways emerge as priority areas for future research.
Ethanol Alters DNMT1/3a/3b Expression Profile, Promotes Persistent DNA Hypomethylation in Human Brain Endothelial Cells and Impairs Late Cortical Angiogenesis.
Siqueira M, Barros M, Almeida PL … +4 more , Dos Santos Heringer L, Mendonça HR, Gomes FCA, Stipursky J
J Neurochem · 2026 Feb · PMID 41668336 · Full text
Exposure of the embryonic central nervous system (CNS) to drugs of abuse, such as ethanol, induces severe and persistent damage to neural cells, contributing to the development of fetal alcohol spectrum disorders (FASD)....
Exposure of the embryonic central nervous system (CNS) to drugs of abuse, such as ethanol, induces severe and persistent damage to neural cells, contributing to the development of fetal alcohol spectrum disorders (FASD). Previously, using a mouse model of FASD, we showed that prenatal alcohol exposure (PAE) directly impairs blood-brain barrier (BBB) development by inducing excessive angiogenesis, altering TJ protein and glucose transporter expression, and modifying the endothelial secretome in the neonatal cerebral cortex. Here, we investigated whether ethanol-induced effects on endothelial cells involve epigenetic reprogramming, specifically through alterations in DNA methylation profiles. Using human brain microcapillary endothelial cells (HBMECs) treated with ethanol, we observed reduced 5-methylcytosine (5mC) labeling intensity and DNA methyltransferase (DNMT) activity, accompanied by changes in the levels of DNMT1, DNMT3a, DNMT3b, methyl-CpG binding protein 2 (MeCP2), and vascular endothelial zinc finger 1 (VEZF1). These effects were associated with altered methylation levels at the promoters of BBB-related genes, including GLUT1 and CLDN5. Notably, ethanol-induced hypomethylation persisted over a prolonged period, even after ethanol withdrawal in HBMEC cultures. Treatment with S-adenosylmethionine (SAM) prevented ethanol-induced hypomethylation in vitro. In vivo, PAE resulted in increased cortical vascular permeability along with persistent vascularization deficits. Together, our findings suggest that ethanol induces long-lasting changes in endothelial cells that may compromise cerebral vasculature formation and function, with modulation of DNA methylation representing a potential molecular mechanism underlying these effects.
Is Higher Antioxidant Capacity an Important Determinant of Cognitive Performance? Editorial Highlight on "Brain Glutathione Levels Associate With Cognitive Performance in Older Adults" by Lee et al.
Duarte JMN
J Neurochem · 2026 Feb · PMID 41668327 · Publisher ↗
Glutathione is a major component of the cellular antioxidant system, providing a means of controlling redox homeostasis and affording protection against oxidative damage. Proton magnetic resonance spectroscopy (MRS) offe...
Glutathione is a major component of the cellular antioxidant system, providing a means of controlling redox homeostasis and affording protection against oxidative damage. Proton magnetic resonance spectroscopy (MRS) offers insights into brain metabolism by enabling the noninvasive quantification of metabolites. Previous studies have demonstrated that the neurotransmitters glutamate and GABA detected by MRS show activity-dependent concentration changes and correlate with cognitive performance. Yet how MRS detected antioxidant capacity, particularly glutathione levels, relates to cognition remains unclear. In this issue, Lee et al. report that higher cortical glutathione levels are associated with better cognitive outcomes in older adults. These findings might contribute to understanding whether glutathione levels index resilience or degeneration. However, observations reported across the literature remain inconsistent, and the observed discrepancies underscore the need for further research using harmonized MRS acquisitions, deeper metabolic and cognitive phenotyping, and longitudinal study designs to clarify the role of cortical glutathione in cognitive trajectories.
Amyloid β-Cholesterol Interplay: Removal of Cholesterol From the Membranes to Catalyze Aggregation and Amyloid Pathology.
Baral R, van Deventer R, Lyubchenko YL
J Neurochem · 2026 Feb · PMID 41665145 · Full text
The interplay between the cholesterol metabolism and assembly of Aβ42 (the 42-residue form of the amyloid-β peptide) peptides in pathological aggregates is considered one of the major molecular mechanisms in the developm...
The interplay between the cholesterol metabolism and assembly of Aβ42 (the 42-residue form of the amyloid-β peptide) peptides in pathological aggregates is considered one of the major molecular mechanisms in the development of Alzheimer's disease (AD). Numerous in vitro studies led to the finding that high cholesterol levels in membranes accelerate the production of Aβ aggregates. The molecular mechanisms explaining how cholesterol localized inside the membrane bilayer catalyzes the assembly of Aβ aggregates above the membrane remain unknown. We addressed this problem by combining different AFM modalities, including imaging and force spectroscopy, with fluorescence spectroscopy. Our combined studies revealed that Aβ42 was capable of removing cholesterol from the membrane. Importantly, physiologically low concentrations of Aβ42 demonstrate such ability. Extracted cholesterol interacts with Aβ42 and accelerates its on-membrane aggregation, which is a molecular mechanism explaining how cholesterol embedded in the membrane accelerates Aβ42 aggregation. The discovered ability of Aβ42 to remove cholesterol from membranes resulted in three major AD-related events. First, free cholesterol catalyzes the assembly of Aβ42 in aggregates, which is the mechanism by which physiologically important Aβ42 monomers are converted into their pathological form. Second, the release of cholesterol from membranes leads to its accumulation in the brain, which is one of the risk factors associated with disease development and progression. Third, cholesterol depletion decreases membrane stiffness, which can result in deterioration of the function of membrane-bound proteins, such as dendritic spine degeneration and, ultimately, synapse loss, a common pathological feature of AD.
N-Truncated Superoxide Dismutase-1 in Cerebrospinal Fluid Is Folded and Active.
Leykam L, Forsberg KME, Andersen PM … +8 more , Brännström T, Weiner S, Rönnholm J, Blennow K, Zetterberg H, Marklund SL, Gobom J, Zetterström P
J Neurochem · 2026 Feb · PMID 41664997 · Full text
Mutations in the antioxidant enzyme superoxide dismutase-1 (SOD1) are a well-established cause of amyotrophic lateral sclerosis (ALS). The mutations promote SOD1 misfolding, resulting in protein aggregation and motor neu...
Mutations in the antioxidant enzyme superoxide dismutase-1 (SOD1) are a well-established cause of amyotrophic lateral sclerosis (ALS). The mutations promote SOD1 misfolding, resulting in protein aggregation and motor neuron degeneration. SOD1 is normally a structurally stable enzyme, and the mechanisms underlying SOD1 misfolding remain poorly understood. Approximately one third of SOD1 in cerebrospinal fluid (CSF) exhibits an N-terminal truncation, the biological significance of which remains unclear. This is remarkable given the dramatic effects ALS-linked C-terminal truncations have on the enzyme. In this study, we identified the truncation site and investigated its impact on SOD1 stability and enzymatic activity. Edman degradation revealed the cleavage site between Asn-26 and Gly-27, generating a 26-residue peptide that was confirmed by mass spectrometry. We analyzed postmortem tissues from different parts of the central nervous system (CNS), including the choroid plexus, and found only trace amounts of N-terminally truncated SOD1. Biochemical characterization of the SOD1 in CSF was done by size exclusion chromatography, ion exchange chromatography, and mass spectrometry. Our findings demonstrate that SOD1 in CSF retains full enzymatic activity, that the N-terminally truncated variant is mainly present in heterodimers with native SOD1 subunits, and that the dimer remains folded and active, with both fragments of the truncated SOD1 fixed after proteolysis. Truncated SOD1 was absent in human plasma. In mice, only transgenically expressed human SOD1 underwent truncation in CSF, whereas endogenous murine SOD1 remained intact. Lastly, the N-terminal truncation does not induce misfolding, unlike the destabilizing effects observed with C-terminal truncations. The location where the truncation takes place and the underlying mechanism could not be identified. Whether the N-truncated SOD1 variant contributes to ALS pathogenesis remains to be determined.
Mild Embryonic Ethanol Exposure Induced Selective Dopaminergic Neurotransmission-Related Changes in Zebrafish: A Review and a Working Hypothesis.
Gerlai R
J Neurochem · 2026 Feb · PMID 41664975 · Publisher ↗
Fetal alcohol spectrum disorders (FASD) result from exposure to alcohol (ethanol) during embryonic development. These diseases cause lifelong struggle for the affected patients. Due to the complex nature of how alcohol a...
Fetal alcohol spectrum disorders (FASD) result from exposure to alcohol (ethanol) during embryonic development. These diseases cause lifelong struggle for the affected patients. Due to the complex nature of how alcohol affects embryonic development, understanding of underlying mechanisms is lacking and treatment options are limited. Reliable diagnostic markers are also unavailable. As a start to bridge this hiatus, animal models have been proposed. One of the most recent ones among these animal models is the zebrafish. In this review, I focus on our own efforts that attempted to model the milder and most prevalent end of the spectrum of this disorder using zebrafish. We discovered that a short period (2 h-long) exposure of the zebrafish embryo to low doses of alcohol (up to 1% vol/vol external bath) at 24th hour post-fertilization led to a lifelong and dose-dependent impairment of social behavior (shoaling) in zebrafish, associated with an apparently selective disruption of dopaminergic neurotransmitter system responses. Here I review these findings and, for example, discuss how analysis of the neurochemistry of the zebrafish brain may aid our understanding of the mechanisms underlying embryonic alcohol-induced abnormalities. I theorize about how a non-selective and pharmacologically complex drug like alcohol may lead to the apparently selective impairment in shoaling and dopaminergic responses in zebrafish. Last, I briefly delineate future plans that may address questions including what specific brain areas, synaptic and molecular mechanisms may underlie the behavioral and neurochemical effects of embryonic alcohol exposure we have observed in zebrafish.
Intrathecal Kappa Free Light Chains in Relation to IgM Synthesis and MRZH Reaction in a Mixed Neurological Cohort.
Auf dem Brinke K, Thust NB, Simou A … +5 more , Lattau SSJ, Lange P, Hansen N, Wallbach M, Fitzner D
J Neurochem · 2026 Feb · PMID 41664964 · Full text
Intrathecal immunoglobulin synthesis is a hallmark of neuroinflammatory diseases. Free kappa light chains (FLCK) in cerebrospinal fluid (CSF) have emerged as a sensitive biomarker of B-cell activity in the central nervou...
Intrathecal immunoglobulin synthesis is a hallmark of neuroinflammatory diseases. Free kappa light chains (FLCK) in cerebrospinal fluid (CSF) have emerged as a sensitive biomarker of B-cell activity in the central nervous system (CNS), yet their relationship to immunoglobulin M (IgM) synthesis and polyspecific antiviral responses remains unclear. We aimed to delineate the diagnostic and immunological significance of FLCK in relation to intrathecal IgM production and the measles-rubella-zoster-herpes (MRZH) antibody reaction across a broad neurological spectrum. We retrospectively analyzed paired CSF and serum samples from 240 patients showing evidence of intrathecal immune activity, defined by oligoclonal bands (OCB), MRZH positivity, or IgM intrathecal fraction (IF) ≥ 10%. Intrathecal synthesis of immunoglobulin classes and FLCK was quantified using Reiber's hyperbolic reference functions. Patients were classified into multiple sclerosis (MS), noninfectious inflammatory neurological disease (NI-IND), infectious neurological disease (IND), neurodegenerative disease (NDD), tumor disease (TUM), and other neurological disease (OND). FLCK intrathecal synthesis (IF ≥ 10%) was detected in 81.7% of patients, including 98% of MS cases. FLCK levels were significantly higher in inflammatory and infectious diseases compared with non-inflammatory conditions (p < 0.001). A subset of OCB-negative but FLCK-positive patients exhibited intrathecal IgM synthesis, suggesting that FLCK capture non-IgG immune responses. In infectious diseases, high FLCK IF correlated with IgM synthesis, whereas in MS and autoimmune disorders, additional immunoglobulin classes likely contributed. FLCK levels also paralleled MRZH reactivity and were highest in patients with multiple viral antibody indices, particularly measles. These findings position FLCK as a quantitative and broadly applicable marker of intrathecal immunoglobulin synthesis across diverse CNS pathologies. FLCK may extend diagnostic sensitivity beyond IgG-based assays and aid in the integrative evaluation of cerebrospinal fluid biomarkers. Prospective studies should evaluate their prognostic value and specificity across neuroinflammatory and infectious diseases.
Motor Neuron Size-Dependent Differences in mRNA Expression of Tropomyosin-Related Kinase Receptor B in Adult Rats.
Martinez RC, Rana S, Gransee HM … +2 more , Sieck GC, Mantilla CB
J Neurochem · 2026 Feb · PMID 41660698 · Full text
Motor neuron plasticity and survival depend on several trophic factors, with signaling via the tropomyosin receptor kinase B (TrkB) receptor being particularly important beyond development and across the lifespan. We hyp...
Motor neuron plasticity and survival depend on several trophic factors, with signaling via the tropomyosin receptor kinase B (TrkB) receptor being particularly important beyond development and across the lifespan. We hypothesized that differences in motor neuron properties may reflect differential trophic influences across motor units within a single motor unit pool. Based on extensive previous characterization of rat phrenic motor neurons (PhMN), somal surface area was used as an indicator of motor unit type (smaller neurons innervating slow-twitch, fatigue-resistant units versus larger neurons innervating fast-twitch, fatigable units). To examine whether TrkB expression reflects these size-related properties, TrkB mRNA transcripts were studied in individual PhMNs labeled retrogradely with Alexa Fluor 488-conjugated cholera toxin subunit β from five adult male Sprague-Dawley rats. Longitudinal sections of the cervical C3-C5 spinal cord (10 μm thick) were processed using fluorescence in situ hybridization (RNAscope) and imaged using confocal microscopy to measure individual PhMN size and full-length TrkB mRNA transcripts in nuclear and cytoplasmic compartments. Across 287 PhMNs, significant size variation existed both within and between animals. Across all animals, somal surface area averaged 4385 ± 1627 μm with mean values per animal ranging from 3544 to 5461 μm. PhMNs were classified into tertiles within each animal based on somal surface area. Individual PhMNs averaged 1070 ± 685 TrkB mRNA transcripts per motor neuron. Larger PhMNs in the upper tertile by size expressed a greater total number of TrkB mRNA transcripts per motor neuron, with values on average threefold higher compared to smaller motor neurons in the lower tertile (p < 0.001). Cytoplasmic and nuclear TrkB mRNA density (transcripts/volume) displayed no significant effect of PhMN somal surface area tertile. Overall, the greater TrkB mRNA levels in larger motor units responsible for higher force, expulsive motor behaviors may underlie their functional adaptations and resilience to injury or disease.
AAV-Driven miR-146a Promotes Neurite Outgrowth and Axonal Regeneration in Cortical Neurons.
Matos VUS, Almeida RA, Ferreira CG … +10 more , Alves MTR, Braga MP, Silva MC, da Silva TF, Guimarães PPG, Soriani FM, Caramelli P, Costa MR, Michel U, Ribas VT
J Neurochem · 2026 Feb · PMID 41657354 · Full text
Adult central nervous system (CNS) neurons exhibit limited intrinsic regenerative capacity, contributing to poor recovery after injury. MicroRNAs (miRNAs) have emerged as key regulators of many biological processes, yet...
Adult central nervous system (CNS) neurons exhibit limited intrinsic regenerative capacity, contributing to poor recovery after injury. MicroRNAs (miRNAs) have emerged as key regulators of many biological processes, yet their therapeutic potential in CNS repair remains incompletely understood. Here, we investigated whether adeno-associated virus (AAV) vector-mediated overexpression of miR-146a enhances neurite and axon regeneration in primary cortical neurons from Wistar rats. We found that AAV.miR-146a significantly increased neurite outgrowth, branching, and long-distance neurite regeneration following scratch injury. Using a microfluidic platform that allows us to selectively lesion axons, we further demonstrated that AAV.miR-146a robustly promotes axonal regrowth. Bioinformatic analyses revealed enrichment of miR-146a target genes involved in transcriptional regulation and synaptic function, with the inflammatory adaptor TRAF6 emerging as a key predicted target. Consistent with these predictions, AAV.miR-146a markedly reduced TRAF6 expression. Together, our results identify miR-146a as a promising therapeutic candidate for enhancing CNS axonal repair and highlight TRAF6 signaling as a potential mechanistic link to its regenerative effects.
Bidirectional Communication Between Astrocytes and Neurons via Extracellular Vesicles: A Multi-Omics Approach.
Hajka D, Żebrowska-Różańska P, Romańczuk K … +6 more , Wiśniewski JR, Łaczmański Ł, Łodej N, Pawlik KJ, Rakus D, Gizak A
J Neurochem · 2026 Feb · PMID 41649029 · Full text
Cells modulate their physiology through multiple mechanisms-cell-cell contacts and autocrine/paracrine signaling, including via extracellular vesicles (EVs). In this study, we exposed mouse hippocampal astrocyte and neur...
Cells modulate their physiology through multiple mechanisms-cell-cell contacts and autocrine/paracrine signaling, including via extracellular vesicles (EVs). In this study, we exposed mouse hippocampal astrocyte and neuron monocultures to EVs from the opposing cell type and subsequently performed RNA sequencing to examine transcriptomic changes. Mass spectrometry was used to analyze the proteomes of EVs from astrocyte and neuron monocultures, as well as from astrocyte-neuron co-cultures, to investigate the molecular basis of EVs-induced transcriptomic alterations and to determine the extent to which cells adjust EV cargo in response to feedback signals. EVs secreted by both cell types induced cell-specific transcriptomic changes in target cells, related to migration, proliferation, differentiation, and energy production. Unique changes in the proteome of EVs from astrocytic-neuronal co-cultures highlighted the dynamic regulation of signaling molecule secretion via cell interactions.
Dynamics and Impact of Repopulating Microglia Following Oligodendroglial Damage.
Di Pietro AA, Thomas L, Pasquini LA
J Neurochem · 2026 Feb · PMID 41645884 · Publisher ↗
Multiple sclerosis is a chronic inflammatory and demyelinating disease that primarily affects young adults. Active demyelination and neurodegeneration have been associated with early microglial and astroglial activation....
Multiple sclerosis is a chronic inflammatory and demyelinating disease that primarily affects young adults. Active demyelination and neurodegeneration have been associated with early microglial and astroglial activation. While reactive microglia (MG) can contribute to tissue damage and exacerbate neurodegeneration, they also play a neuroprotective role by clearing debris through phagocytosis and secreting growth factors that support repair. The aim of this study was to evaluate the effects of MG depletion and repopulation on the response to lysophosphatidylcholine-induced oligodendroglial damage using an in vitro model previously characterized by our laboratory. Since microglial development and survival critically depend on colony-stimulating factor-1 receptor (CSF-1R) signaling, we employed CSF-1R inhibition with BLZ945 to effectively deplete MG. Results show that repopulation occurs even in demyelinating conditions and, at early time points, results in MG exhibiting a morphology indicative of a less activated phenotype. Despite having higher phagocytic activity, early repopulating MG are few and thus unable to efficiently clear myelin debris. However, these repopulating MG still demonstrated to induce oligodendroglial differentiation. Studies using conditioned media revealed that early repopulating MG release factors into the environment which promote oligodendroglial progenitor cell viability and facilitate oligodendroglial differentiation in a demyelinating context, an effect not observed in neurons. Interestingly, our in vitro results show a close correlation with in vivo findings previously reported and demonstrate the relevance of our model in developing therapies for demyelinating diseases. These findings underscore both the potential and limitations of microglial modulation aimed at eliminating pro-inflammatory profiles and promoting repopulation with pro-regenerative characteristics.
Aberrant Protein S-Nitrosylation Mimics the Effect of Rare Genetic Mutations in Neurodegenerative Diseases.
Wang Y, Lipton SA
J Neurochem · 2026 Feb · PMID 41635116 · Full text
Neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease/Lewy body dementia (PD/LBD), and amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) are driven by complex interactions of gen...
Neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease/Lewy body dementia (PD/LBD), and amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) are driven by complex interactions of genetic and environmental factors. While genome wide association studies (GWAS) have uncovered a number of risk gene variants (e.g., APOE, SNCA [encoding α-synuclein], and protein disulfide isomerase [PDI]), these genetic factors alone cannot fully explain disease onset or progression. Emerging evidence suggests that post-translational modifications of proteins, particularly S-nitrosylation (SNO), act as a critical link between environmental stress and neurodegenerative pathology. Here, we review data showing that while physiological protein SNO regulates diverse neuronal processes, aberrant SNO, occurring very commonly in the diseased brain, can disrupt protein function in ways that mimic the deleterious effects of rare genetic mutations. We advance the concept of "mutational mimicry," whereby aberrant SNO of key neuronal or glial proteins reproduces the functional consequences of known specific genetic mutations, ultimately converging on common pathways of synaptic dysfunction emanating from mitochondrial and metabolic impairment, proteostasis, neuroinflammation, and so on. Supporting this framework, proteomic analyses show significant overlap between abnormally S-nitrosylated proteins in diseased brains and known genetic risk factors in AD and PD/LBD as well as in ALS. By linking redox biology to human genetics, this review highlights how environmental factors can phenocopy or enhance genetic susceptibilities. Understanding this convergence not only provides novel insight into disease mechanisms but also suggests new therapeutic targets to intervene in these convergent pathways with the goal of halting neurodegenerative processes.
Correction to "Early Life Mild Adversity Affects in a Sexually Dimorphic Way the Oxytocinergic System Reducing Close Social Interaction in Adult Male Rats".
J Neurochem · 2026 Feb · PMID 41631583 · Full text
Abstract loading — click title to view on PubMed.
Zinc-Mediated Lysosomal Destabilization Links Mitochondrial Damage to Neuronal Death in a Cellular MPP Model of Parkinson's Disease.
Lee HS, Kang SA, Eom JW … +3 more , Kim MS, Kim JS, Kim YH
J Neurochem · 2026 Feb · PMID 41622607 · Full text
Dysregulation of autophagy and lysosomal function is central to Parkinson's disease (PD), yet the upstream mechanisms leading to lysosomal failure remain unclear. Across primary mouse cortical neurons, MT-3 deficient pri...
Dysregulation of autophagy and lysosomal function is central to Parkinson's disease (PD), yet the upstream mechanisms leading to lysosomal failure remain unclear. Across primary mouse cortical neurons, MT-3 deficient primary mouse astrocytes, human iPSC-derived midbrain dopaminergic neurons, and Rho CHO cells lacking mitochondrial respiration, we investigated how mitochondrial stress perturbs zinc (Zn) homeostasis and lysosomal integrity. We identify intracellular zinc as a critical mediator linking mitochondrial dysfunction to lysosomal membrane permeabilization (LMP) and neuronal death. Inhibition of mitochondrial complex I by 1-methyl-4-phenylpyridinium (MPP) elevated reactive oxygen species (ROS) and intracellular zinc, jointly driving LMP. Blocking either ROS or zinc markedly attenuated lysosomal damage and cell death, demonstrating that both act upstream of LMP. To define zinc regulation, we examined metallothionein-3 (MT-3), a brain-enriched zinc-binding protein. MT-3-deficient astrocytes were more vulnerable to MPP and zinc overload (ZnCl) but paradoxically resistant to hydrogen peroxide (HO), suggesting that MT-3 buffers cytosolic zinc during mitochondrial injury or extracellular zinc influx yet can release bound zinc under oxidative conditions. Using Rho cells, we show that MPP toxicity depends on mitochondrial ROS, as loss of mitochondrial function nearly abolished cell death. However, Rho cells were highly sensitive to ZnCl and HO and exhibited markedly reduced lysosomal abundance, indicating limited capacity to sequester zinc and increased susceptibility to zinc-mediated injury. These findings support a coordinated system in which lysosomes and zinc-binding proteins maintain zinc homeostasis. When cytosolic zinc rises, its accumulation within lysosomes induces LMP and accelerates cell death. Collectively, our results identify intracellular zinc as an upstream trigger of lysosomal dysfunction and neurodegeneration. Zinc-mediated LMP provides a mechanistic link between mitochondrial injury, impaired autophagic flux, and α-synuclein pathology in PD. Enhancing zinc homeostasis and lysosomal resilience may offer promising therapeutic strategies.
Astrocyte Regulation of Spinal Circuit Function.
Duff MK, Li MJ, Nimmerjahn A
J Neurochem · 2026 Feb · PMID 41612623 · Full text
The spinal cord stands as a crucial nexus in the central nervous system (CNS), integrating and modulating signals that ultimately shape our everyday interactions with the world. Its gray matter is arranged into discrete...
The spinal cord stands as a crucial nexus in the central nervous system (CNS), integrating and modulating signals that ultimately shape our everyday interactions with the world. Its gray matter is arranged into discrete laminae spanning the dorsal-ventral axis that encompass circuit-specific modalities. Concurrently, extensive interconnected interneuron networks within and between these laminae confer remarkable flexibility in the behavioral outputs for a given input. The flexibility of spinal cord information processing in light of its organized architecture makes it a particularly intriguing region to explore the neuronal computations underlying behaviors, particularly as they relate to neurological dysfunction. At the same time, astrocytes engage in highly dynamic interactions with underlying neuronal circuitries, suggesting they may add another dimension to spinal cord information processing. Technical limitations specific to the spinal cord have long limited our ability to interrogate the relationship between astrocyte-neuron interactions and ongoing spinal cord function. In this review, we highlight emerging insights-particularly those from recent in vivo studies-that illustrate astrocytes actively shape spinal cord behavioral outputs in both health and disease. We briefly review the spinal cord's neuronal organization to provide a structural foundation for assessing the relative spatial relationship between astrocyte and neuron activity as it relates to different spinal cord outputs. Within this architectural framework, we review growing evidence that spinal cord astrocytes respond to activity associated with spinal cord function and, in turn, modulate underlying neuronal circuits to alter future behavioral outputs. Moreover, we propose an overall conceptual framework for understanding circuit-specific spinal cord modulations through the lens of astrocyte-neuron interactions and underscore how it can be leveraged to uncover novel ways of targeting spinal cord disease states. Finally, we put forth key outstanding questions related to this conceptual framework and emphasize the technological advances that will facilitate future studies addressing them.
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