Journal of Neurochemistry最新文献

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.

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.

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.

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.

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.

Currently, no effective treatment exists for injuries at the interface between the CNS/PNS, largely due to their complex pathophysiology and the limited efficacy of single-target therapies. To address this challenge, we investigated a novel combinatorial therapeutic strategy integrating surgical VRR with fibrin sealant biopolymer (FSB) and DMT in a rat model of ventral root avulsion VRA. DMT was extracted from Mimosa tenuiflora roots and structurally characterized using standard analytical methods. Adult female Lewis rats underwent unilateral L4-L6 VRA and received daily DMT treatment (1, 2.5, or 5 mg/kg; i.p) for 2 weeks to determine the optimal therapeutic dose. Subsequently, the identified optimal DMT dose was combined with VRR, and animals were evaluated 2 weeks post-injury. Outcome measures encompassed quantitative assessments of neuronal survival, glial reactivity, synaptic preservation, and differential gene expression of neurotrophic factors (GDNF, FGF-2, VGF-A) and anti-apoptotic genes (Bcl-2, Bcl-XL). Extracted DMT met all structural and analytical criteria for experimental use. Proximal axotomy led to substantial MN loss (78%), accompanied by pronounced glial reactivity and synaptic detachment. DMT at 1 mg/kg yielded the strongest neuroprotective profile, significantly enhancing MN survival, reducing glial reactivity, and preserving pre-synaptic boutons. Notably, these effects were further potentiated when DMT treatment was combined with VRR. Moreover, the combined VRR + DMT therapy significantly upregulated GDNF expression, indicating a synergistic effect on neurotrophic support. Overall, our findings suggest that DMT is a promising neuroprotective agent for treating MN degeneration following CNS/PNS interface injuries, particularly when integrated into a combinatorial therapeutic strategy.

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.

We describe the development of neurochemistry in Brazil, Argentina, Uruguay, and Chile in the XX century through Latin American scientists who pioneered the discipline in their countries. In addition, we analyze the research groups that succeeded the pioneers and the fields explored in greater depth in different countries. We examine the history of glial cell research and the efforts made despite financial constraints. We also highlight the role of the International Society of Neurochemistry (ISN) in the history of neurochemistry in Latin America. A special section is dedicated to neurochemistry in Venezuela, given its significant role in the past.