Journal of Neurochemistry最新文献

Androniki, R., P. Lydia, G. Sofia, K. Theodora, S. Fotini, and S. Antonios. 2025. “Early Life Mild Adversity Affects in a Sexually Dimorphic Way the Oxytocinergic System Reducing Close Social Interaction in Adult Male Rats.” Journal of Neurochemistry 169, no. 12: e70326. https://doi.org/10.1111/jnc.70326.

In the paper by Androniki et al. (2025), the author names appeared incorrectly. They should read:

Androniki Raftogianni, Lydia Pavlidi, Sofia Galeou, Theodora Kalpachidou, Fotini Stylianopoulou, Antonios Stamatakis

The author names have been corrected on the original article.

We apologize for this error.

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.

Oligodendrocyte maturation and myelination are critical processes in human neurodevelopment, and their dysregulation is linked to numerous neurological disorders. While model organisms have provided insight into these processes, human-specific regulatory mechanisms remain poorly understood. This study investigated human THAP9, a protein homologous to the Drosophila P-element transposase, whose function in oligodendrocytes remains unknown. An analysis of RNA-sequencing data and H3K27ac ChIP-sequencing data from oligodendrocyte progenitor cells (OPCs) and mature oligodendrocytes (MOs) revealed significant upregulation of THAP9 during oligodendrocyte maturation. Co-expression analysis demonstrated a strong correlation with established markers of oligodendrocyte development, including myelin-associated genes (MOG, MBP) and key transcriptional regulators (PDGFRA, SOX5, SOX6, SOX11). THAP9 lacks homologues in mice, highlighting potential human-specific mechanisms in oligodendrocyte development and emphasising the importance of studying species-specific factors in neurodevelopment. Our findings suggest that THAP9 is a novel human-specific regulator of oligodendrocyte maturation and opens new avenues for studying myelination disorders.

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.

Ex vivo acute brain slice is a popular technique in neuroscience research with many variations. While many variations are currently used by labs around the world, no study has comprehensively examined the impact of these variations on the quality of the acute brain slice preparation. In this study, we compared different animal sacrifice methods (decapitation or transcardial perfusion) and cutting solution (normal or sucrose artificial cerebrospinal fluid). Brain slices were prepared from 10 to 12 weeks old male Wistar rats (Rattus norvegicus). Neuronal population was quantified by immunohistochemistry against various neuronal markers. Neuronal dynamics was evaluated by in vitro electrophysiology using two acute epilepsy models-zero-magnesium and 4-aminopyridine. We found that the method of brain slice preparation significantly affected the quality of the brain slice preparation. In general, the combination of transcardial perfusion and sucrose artificial cerebrospinal fluid produces the optimal brain slice preparation. The slices prepared with transcardial perfusion and sucrose aCSF had higher preservation of inhibitory interneurons and subsequently less successful induction of acute epileptiform activity. We also found that loss of inhibitory GABAergic neurons during brain slice preparation is primarily due to oxidative damage. Limiting oxidative stress is an effective neuroprotection strategy to prevent loss of inhibition in brain slice preparation. In conclusion, consideration of brain slice preparation method is crucial in preserving inhibitory GABAergic neurons and the degree of inhibition in the slice. Loss of inhibitory interneuron due to oxidative stress significantly affects quality of brain slice preparation and subsequent ex vivo epileptiform activity induction and dynamics.

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.

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.

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.

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 Rho⁰ CHO cells lacking mitochondrial respiration, we investigated how mitochondrial stress perturbs zinc (Zn²⁺) 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 (ZnCl₂) but paradoxically resistant to hydrogen peroxide (H₂O₂), suggesting that MT-3 buffers cytosolic zinc during mitochondrial injury or extracellular zinc influx yet can release bound zinc under oxidative conditions. Using Rho⁰ cells, we show that MPP⁺ toxicity depends on mitochondrial ROS, as loss of mitochondrial function nearly abolished cell death. However, Rho⁰ cells were highly sensitive to ZnCl₂ and H₂O₂ 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.

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.