Journal Of Neurochemistry[JOURNAL]
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200 papers
Combined Neuroprotective Effects of N,N-Dimethyltryptamine and Ventral Root Reimplantation Following Spinal Root Avulsion in Rats.
Aponte PAC, Montoya EH, Mazali IO … +5 more , Sussulini A, Barraviera B, Ferreira RS, Cartarozzi LP, de Oliveira ALR
J Neurochem · 2026 Feb · PMID 41612619 · Full text
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...
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.
Integrative Genomic Analysis Identifies THAP9 as a Human-Specific Regulator of Oligodendrocyte Differentiation.
Bhardwaj T, Patel D, Majumdar S
J Neurochem · 2026 Feb · PMID 41612596 · Publisher ↗
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 pr...
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.
Neuroscience in Latin America Five Decades of Flourishing Neurochemistry in the Region.
Pasquini JM, Gomes FCA, de Melo Reis RA … +3 more , Cassina P, Barbeito L, Olivera S
J Neurochem · 2026 Feb · PMID 41607077 · Publisher ↗
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 rese...
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.
Inhibitory GABAergic Neuron Loss due to Oxidative Damage During Ex Vivo Acute Brain Slice Preparation Influences Genesis and Dynamics of Epileptiform Activity.
Chan F, Hazra A, Jayasekera A … +10 more , Huang K, Whyte S, Telford-Cooke L, Lakhani K, Li X, Shields R, Kosim A, Su D, Murray C, Cunningham MO
J Neurochem · 2026 Feb · PMID 41603127 · Full text
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...
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.
From Neuron-Centric to Glia-Centric: How Aging Glial Networks Drive Neurodegenerative Disease.
Hayashide LS, Pessoa B, Dias G … +3 more , Pontes B, Pinto RS, Diniz LP
J Neurochem · 2026 Jan · PMID 41591255 · Full text
The traditional neuron-centric view of neurodegeneration is being replaced by a glial network-based framework. This shift recognizes that age-related dysfunction in non-neuronal cells critically shapes neuronal vulnerabi...
The traditional neuron-centric view of neurodegeneration is being replaced by a glial network-based framework. This shift recognizes that age-related dysfunction in non-neuronal cells critically shapes neuronal vulnerability and circuit resilience. Aging, the major risk factor for neurodegenerative diseases, is increasingly associated with the accumulation of senescent glial cells, particularly astrocytes, which emerge as early and active drivers of central nervous system decline. This review highlights astrocytic senescence as a key mechanism linking brain aging to neurodegeneration. Senescent astrocytes exhibit hallmark features including stable cell cycle arrest, mitochondrial dysfunction, and the acquisition of a senescence-associated secretory phenotype (SASP), which disrupts synaptic integrity, impairs proteostasis, and sustains chronic neuroinflammation. These alterations often precede overt neuronal loss in disorders such as Alzheimer's and Parkinson's disease. We discuss core hallmarks and biomarkers of glial senescence, emphasizing integrative strategies combining functional assays and molecular markers. We further highlight circulating SASP-related factors and extracellular vesicles as translational indicators of systemic senescence. Finally, we examine emerging senotherapeutic approaches aimed at restoring glial homeostasis, including senolytics, senomorphics, and CAR-T-based immunotherapies. Targeting glial senescence and interglial communication therefore represents a promising, though complex, paradigm-shifting avenue for delaying brain aging and mitigating neurodegenerative progression.
Correction to "Cannabinoid Ligand-Mediated Glycogen Depletion in Astrocytes Is Associated With Increased Intracellular Calcium, Energy Metabolism, and Membrane Dynamics".
J Neurochem · 2026 Jan · PMID 41589830 · Full text
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TFG p.G269V Mutation Disrupts Motor Neuron Function in iPSC-Derived Models via Wnt Signaling Dysregulation.
Mu Z, Wang J, Xiao T … +8 more , Chen K, Chen X, Liu Q, Huang J, Li Y, Chen J, Wu Y, Liu F
J Neurochem · 2026 Jan · PMID 41572572 · Publisher ↗
Charcot-Marie-Tooth disease (CMT), an inherited neuropathy characterized by progressive distal muscle weakness and atrophy, is associated with axonal impairment. Although mutations in the TRK-fused gene (TFG) have been l...
Charcot-Marie-Tooth disease (CMT), an inherited neuropathy characterized by progressive distal muscle weakness and atrophy, is associated with axonal impairment. Although mutations in the TRK-fused gene (TFG) have been linked to both CMT and hereditary spastic paraplegia, their pathogenic mechanisms remain poorly understood. Previously, we have demonstrated that the TFG p.G269V mutation causes progressive muscle weakness in patients, impairs neurite outgrowth in primary cultured mouse neurons, and induces neuronal apoptosis in zebrafish, suggesting a conserved role in neurodevelopment. To investigate its effects in human models, we established induced pluripotent stem cells (iPSCs) from patients carrying the mutation and generated homologous correction lines using CRISPR/Cas9 editing. Both cell lines differentiated into motor neurons (MNs). Although neuronal differentiation and the expression of maturation markers were comparable, the patient-derived MNs exhibited significant axonal shortening and TFG-associated insoluble material. Electrophysiological assessment revealed functional deficits, including reduced spontaneous and evoked action potential frequencies and elevated rheobase. Transcriptomic analysis revealed dysregulation of Wnt signaling, and pharmacological inhibition of this pathway further exacerbated the loss of neuronal excitability. Our findings indicate that the TFG p.G269V mutation autonomously disrupts MN morphology and function and that these defects can be reversed using genetic correction. Moreover, dysregulated Wnt signaling may contribute to the pathophysiology of TFG-associated neuropathy.
Prosaposin Is Cleaved Into Saposins by Multiple Cathepsins in a Progranulin-Regulated Fashion.
Hodul M, Lane-Donovan C, Cheang ES … +5 more , Gao V, Sampognaro PJ, Mambou EA, Yang Z, Kao AW
J Neurochem · 2026 Jan · PMID 41572567 · Full text
Prosaposin (PSAP) is a lysosomal protein that plays a key role in sphingolipid metabolism. PSAP is cleaved into four bioactive disulfide-rich saposins (SapA, SapB, SapC, and SapD) that catalyze sphingolipidases to promot...
Prosaposin (PSAP) is a lysosomal protein that plays a key role in sphingolipid metabolism. PSAP is cleaved into four bioactive disulfide-rich saposins (SapA, SapB, SapC, and SapD) that catalyze sphingolipidases to promote sphingolipid breakdown. Maintaining optimal levels of PSAP and saposins is crucial for proper lysosomal function and sphingolipid homeostasis, and PSAP dysfunction is associated with juvenile-onset lysosomal storage disorders and age-associated neurodegenerative disorders. Despite this, the mechanism by which saposins are released from PSAP, and thus available to modulate sphingolipidases, sphingolipid homeostasis, and downstream lysosomal function, is not well understood. Here, we performed a comprehensive study to identify lysosomal enzymes that regulated prosaposin cleavage into saposins. In vitro cleavage assays identified multiple enzymes that could process human prosaposin into multi- and single-saposin fragments. We confirmed the role of cathepsins D and B in PSAP processing and identified several additional lysosomal proteases (cathepsins E, K, L, S, V, G, and asparagine-specific endopeptidase) that were able to process PSAP in distinctive, pH-dependent manners. In addition, we found that PGRN and multi-granulin fragments (MGFs) directly regulated the cleavage of PSAP by cathepsin D. With this study, we have shown that multiple cathepsins, PGRN, and MGFs work in concert to produce saposins under different conditions, which could present novel opportunities to modulate saposin levels in disease.
Extracellular Vesicle-Derived microRNAs as Fluid Biomarkers in Neurodegenerative Diseases: A Systematic Review.
Zaman A, Drake SS, Fournier AE
J Neurochem · 2026 Jan · PMID 41572495 · Full text
Given the absence of curative treatments for neurodegenerative diseases, early detection and therapeutic intervention are critical to slowing disease progression. Extracellular vesicles (EVs) have emerged as promising bi...
Given the absence of curative treatments for neurodegenerative diseases, early detection and therapeutic intervention are critical to slowing disease progression. Extracellular vesicles (EVs) have emerged as promising biomarkers for neurodegeneration, owing to their accessibility in bodily fluids and dynamic molecular cargo, including microRNAs (miRNAs). The last decade has seen accumulating evidence for miRNA dysregulation in circulating EVs from people with neurodegenerative diseases; however, assessing reproducibility between studies remains challenging, largely due to clinical and methodological heterogeneity. In this systematic review, we comprehensively searched the MEDLINE database for studies investigating miRNA expression in biofluids from people with neurodegenerative diseases. We extracted miRNA expression data from 185 peer-reviewed publications, published until June of 2025, reporting altered miRNA levels in fluid-derived EVs from people with neurodegenerative diseases. We consolidated results between studies to identify the most frequently dysregulated miRNAs across diseases, with a focus on Alzheimer's disease, Parkinson's disease, mild cognitive impairment, multiple sclerosis, amyotrophic lateral sclerosis, frontotemporal dementia, stroke, traumatic brain injury, and schizophrenia. Evaluating tissue specificity of frequently dysregulated miRNAs revealed enrichment of select miRNAs in the nervous system relative to blood and immune compartments. Summarizing miRNA regulation across biofluids emphasized consistencies between cerebrospinal fluid and plasma, but not serum. We highlight circulating miRNAs that may be reflective of neuropathology, including miR-143-3p, miR-127-3p, miR-9-5p, miR-15a-5p, and miR-125b-5p. Finally, we provide a repository of miRNA expression data from over 30 neurodegenerative conditions which can be exploited to further investigate miRNA regulation in diseases of interest.
Alterations in Both Caliber and Myelination of Callosal Axons Elicited by Ubiquitous Genetic Ablation of c-Jun Amino-Terminal Kinase 3 (JNK3).
Bardile CF, Priego M, Sidik H … +4 more , Tano V, Langley SR, Pouladi MA, Morfini G
J Neurochem · 2026 Jan · PMID 41567033 · Publisher ↗
Myelination is a fundamental process supporting appropriate motor, sensory, and cognitive functions. During development, oligodendrocyte progenitor cells (OPCs) proliferate, migrate, and gradually differentiate into matu...
Myelination is a fundamental process supporting appropriate motor, sensory, and cognitive functions. During development, oligodendrocyte progenitor cells (OPCs) proliferate, migrate, and gradually differentiate into mature oligodendrocytes, which produce and assemble myelin sheets that insulate axons in the mammalian central nervous system. Recent evidence suggested a regulatory role of the protein kinase JNK1, one of three mammalian JNK isoforms, on the proliferation and differentiation of OPCs, but whether other JNK isoforms modulate these and other cellular events contributing to myelination has not yet been explored. Building on results from an unbiased proteomic analysis, our studies here revealed increased numbers of OPCs, but not mature oligodendrocytes, in the corpus callosum of mice featuring germline ablation of the JNK3 isoform. Ultrastructural analyses further showed an increased proportion of small caliber callosal axons in these mice, as well as thinning of their myelin sheaths. These alterations were accompanied by reduced phosphorylation of heavy chain subunits of neurofilaments (NFs), major cytoskeletal elements linking myelin to the regulation of axonal caliber. Collectively, our findings reveal previously unrecognized effects of JNK3 deletion on OPC proliferation, NF phosphorylation, callosal axon caliber, and myelin thickness in vivo, suggesting a potential involvement of this kinase on myelinogenesis and/or myelin maintenance.
Correction to "Essential Roles of Heparan Sulfate Endosulfatase Sulf1 in Reward and Aversion Learning Through Distinct Dopamine D1 and D2 Receptor Pathways in Male Mice".
J Neurochem · 2026 Jan · PMID 41560440 · Full text
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Proteomic Landscape of Sweat Glands in Neuronal Intranuclear Inclusion Disease Reveals a Pathogenic Triad of Abnormal Autophagy, Mitochondrial Dysfunction, and a Failed Oxidative Stress Response.
Wang A, Tai HF, Zhang K … +8 more , Zhou Y, Sun W, Guo ZG, Sun HD, Jian F, Wang XG, Pan H, Zhang ZQ
J Neurochem · 2026 Jan · PMID 41556371 · Publisher ↗
Neuronal Intranuclear Inclusion Disease (NIID), caused by GGC repeat expansions in the NOTCH2NLC gene, has a poorly understood molecular pathogenesis. This study aimed to systematically delineate the molecular pathology...
Neuronal Intranuclear Inclusion Disease (NIID), caused by GGC repeat expansions in the NOTCH2NLC gene, has a poorly understood molecular pathogenesis. This study aimed to systematically delineate the molecular pathology of NIID for the first time by employing an unbiased proteomic approach in sweat gland tissue. We isolated sweat gland tissue from 20 NIID patients and 6 healthy controls via Laser Capture Microdissection and performed in-depth proteomic analysis using data-independent acquisition mass spectrometry, followed by functional annotation and mechanistic prediction through bioinformatics analyses, including Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and Ingenuity Pathway Analysis. A total of 265 differentially expressed proteins were identified. Functional enrichment analysis revealed a pathological network composed of three core dysfunctions: (1) widespread mitochondrial dysfunction, evidenced by the general downregulation of proteins associated with energy metabolism and mitochondrial structure; (2) multidimensional autophagy failure, characterized by autophagic flux blockage (macroautophagy failure) and the predicted inhibition of Chaperone-Mediated Autophagy; and (3) a paradoxical and ineffective oxidative stress response, demonstrating a functional uncoupling between the upstream NRF2 activation signal and the execution of the downstream antioxidant pathway. The cellular validation confirmed that the pathogenic uN2CpolyG protein causes the downregulation of core hub proteins, substantiating the molecular pathology observed in patient tissue. Furthermore, a signal decoupling state was identified in the pivotal PI3K-Akt survival pathway. This study provides the first systematic proteomic view of NIID pathology in sweat gland tissue, substantiating that its core pathology is a self-reinforcing vicious cycle of mitochondrial dysfunction, abnormal autophagy, and oxidative stress imbalance. These findings offer a robust molecular framework for understanding GGC repeat expansion pathogenesis and illuminate new therapeutic avenues targeting these interconnected pathways.
Sevoflurane Inhibits Layer 5 Pyramidal Neurons via Kv1.2-Dependent Modulation of Subthreshold Currents.
Araujo AS, de Queiroz GM, Silva SRB … +2 more , Treptow W, Leao KE
J Neurochem · 2026 Jan · PMID 41556370 · Full text
General anesthetics reduce cortical activity and disrupt consciousness, yet the molecular mechanisms underlying their effects on neocortical neurons remain incompletely understood. Recent evidence implicates layer 5 pyra...
General anesthetics reduce cortical activity and disrupt consciousness, yet the molecular mechanisms underlying their effects on neocortical neurons remain incompletely understood. Recent evidence implicates layer 5 pyramidal neurons (L5 PNs) as critical targets, particularly through anesthetic-induced decoupling of distal apical dendritic inputs from somatic output. While several anesthetics impair L5 excitability, the ion channels mediating this effect have yet to be clearly identified. Voltage-gated Kv1.2 potassium channels have emerged as compelling candidates due to their high expression in L5 PNs and their known potentiation by volatile anesthetics. In this study, we investigated the effects of low-dose sevoflurane (~22 μM) on L5 PNs in the primary auditory cortex of adult mice using whole-cell patch-clamp recordings. Sevoflurane significantly suppressed firing and induced cell-type-specific changes in membrane properties: depolarizing the resting potential in type A neurons and increasing input resistance and altering action potential shape in type B neurons. Application of the selective Kv1.2 blocker TsTX-Kα partially reversed these effects at subthreshold membrane potentials, implicating Kv1.2 channel potentiation in the modulation of neuronal excitability. Supporting that view, NEURON simulations using a detailed biophysical model of thick-tufted L5b pyramidal neurons further revealed a significant sevoflurane-induced increase in persistent K conductance, consistent with Kv1.2 potentiation. To our knowledge, this is the first study to demonstrate distinct, cell-type-specific effects of sevoflurane on L5 PNs and to establish the functional relevance of Kv1.2 channel potentiation in anesthetic suppression of cortical excitability. These findings offer new insights into the molecular actions of sevoflurane and support a broader role for Kv1.2 channels in mediating anesthetic-induced outcomes.
Isoform-Specific Splicing of ANK2 by PTBP2 Orchestrates Retinal Pigment Epithelial-to-Neuron Fate Conversion.
Ma YX, Zhang YK, Li J … +1 more , Zhu BL
J Neurochem · 2026 Jan · PMID 41555757 · Publisher ↗
Direct lineage reprogramming represents a promising strategy to convert somatic cells into neurons, offering regenerative potential. While transcription factor-based approaches have been extensively studied, the role of...
Direct lineage reprogramming represents a promising strategy to convert somatic cells into neurons, offering regenerative potential. While transcription factor-based approaches have been extensively studied, the role of post-transcriptional regulation, particularly alternative splicing (AS), in neuronal fate acquisition remains poorly defined. Here, we demonstrate that the concurrent knockdown of the splicing regulator PTBP2 and the barrier protein p53 enhances the neuronal conversion of human retinal pigment epithelial (hRPE-19) cells when combined with ASCL1 and miR-9/9*-124 (AMnp). Transcriptomic and splicing analyzes reveal that PTBP2 depletion induces widespread AS changes, most notably promoting near-complete inclusion of exon 36 in the ANK2 gene, which encodes a key regulator of axon initial segment assembly. Functional and rescue assays confirm that loss of exon 36 significantly impairs neuronal induction, whereas re-expression restores neuronal conversion efficiency, establishing ANK2 isoform switching as a mechanistic requirement for reprogramming. Moreover, photoreceptor markers expression in AMnp-reprogrammed neurons suggests partial photoreceptor-like features potentially reflecting residual epigenetic memory, with chromatin remodeling potentially cooperating with splicing to influence subtype specification. These findings identify the PTBP2-ANK2 splicing axis as an isoform-specific molecular switch for RPE-to-neuron conversion, offering a strategy to enhance the precision and efficiency of neuronal reprogramming.
Oxidative Stress-Related Serum Extracellular Vesicle miRNAs Indicate Symptom Severity and Cognitive Decline in Parkinson's Disease.
Belickienė V, Pranckevičienė A, Radžiūnas A … +3 more , Strigauskaitė A, Laucius O, Vaitkienė P
J Neurochem · 2026 Jan · PMID 41549541 · Full text
Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by motor and non-motor symptoms, including cognitive decline and reduced quality of life. Identifying reliable biomarkers for disease pro...
Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by motor and non-motor symptoms, including cognitive decline and reduced quality of life. Identifying reliable biomarkers for disease progression and symptom severity remains a critical challenge. In this study, levels of oxidative stress-related microRNAs (miR-24-3p, miR-103a-3p, miR-320a-3p, miR-494-3p, miR-126-5p, and miR-543) within blood serum extracellular vesicles (EVs) were examined in a cohort of 93 PD patients to assess their associations with cognitive function, symptom severity, quality of life, and other clinical characteristics. The methods included microRNA extraction from blood serum EVs, followed by cDNA synthesis and RT-qPCR for expression analysis. Upregulation of miR-126-5p, as well as downregulation of miR-24-3p showed the strongest associations with symptom severity and cognitive decline, whereas downregulated miR-320a-3p levels correlated with patient-reported quality of life in PD patients. Downregulation of miR-103a-3p, and miR-543 expression showed slight associations with motor symptoms, cognitive function, and quality of life domains; however, some of these associations lacked statistical power. These findings indicate that specific microRNA expression profiles in extracellular vesicles are associated with PD symptom severity and progression, supporting their further evaluation as biomarkers in larger independent cohorts.
Unveiling the Proteomic Landscape of Extracellular Vesicles: Implications for Neurodegeneration and Neuroprotection.
Bernal-Vicente BN, Ponce I, Ríos-Castro E … +2 more , Moreno-Castilla P, Tovar-Y-Romo LB
J Neurochem · 2026 Jan · PMID 41532955 · Full text
Extracellular vesicles (EVs) are instrumental mediators of intercellular communication and molecular exchange in neurodegenerative and neurovascular diseases. This review integrates recent advances in EV proteomics to el...
Extracellular vesicles (EVs) are instrumental mediators of intercellular communication and molecular exchange in neurodegenerative and neurovascular diseases. This review integrates recent advances in EV proteomics to elucidate their roles in Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), traumatic brain injury (TBI), and ischemic stroke. Across these conditions, EVs carry disease-relevant proteins that reflect and influence key pathological processes such as synaptic dysfunction, neuroinflammation, blood-brain barrier (BBB) disruption, and cell death. Proteomic profiling of brain- and biofluid-derived EVs has uncovered specific biomarkers and signaling pathways, ranging from tau and α-synuclein in AD and PD to mutant SOD1 in ALS and complement activation in stroke and TBI. Moreover, cell-type-specific EVs (e.g., from neurons, astrocytes, microglia, and stem cells) have been shown to exert either protective or deleterious effects, modulating apoptosis, axonal regeneration, and immune responses. Recent evidence highlights the translational potential of EVs as non-invasive biomarkers and therapeutic vectors across multiple disorders. By mapping shared and divergent proteomic signatures in EVs, we review the mechanistic relevance and clinical utility of EVs in neurodegeneration and CNS injury.
Dissociation of the mTOR Protein Interaction Network Following Neuronal Activation Is Altered by Shank3 Mutation.
Wehle DT, Brown EA, Stamenkovic V … +3 more , Kniffen B, Harsh FM, Smith SEP
J Neurochem · 2026 Jan · PMID 41532697 · Full text
The mechanistic target of Rapamycin (mTOR) kinase pathway plays critical roles in neuronal function and synaptic plasticity, and its dysfunction is implicated in numerous neurological and psychiatric disorders. Tradition...
The mechanistic target of Rapamycin (mTOR) kinase pathway plays critical roles in neuronal function and synaptic plasticity, and its dysfunction is implicated in numerous neurological and psychiatric disorders. Traditional linear models depict mTOR signaling as a sequential phosphorylation cascade, but accumulating evidence supports a model that includes signaling through dynamic protein-protein interaction networks. To examine how neuronal mTOR signaling networks discriminate between distinct stimuli, we quantified phosphorylation events and protein co-association networks in primary mouse cortical neurons. Unexpectedly, neuronal mTOR activation by IGF or glutamate triggered dissociation-rather than the anticipated assembly-of protein complexes involving mTOR complex 1 (TORC1), mTOR complex 2 (TORC2), and translational machinery, distinguishing neurons from proliferative cells. Applying in vitro homeostatic scaling paradigms revealed distinct combinatorial encoding of synaptic scaling direction: both up- and down-scaling induced dissociation of translational complexes, but downscaling uniquely included dissociation of upstream pathway regulators. Cortical neurons from Shank3B knockout mice, modeling autism-associated Phelan-McDermid Syndrome, displayed baseline hyperactivation of the mTOR network, which reduced the dynamic range of protein interaction network responses to homeostatic synaptic scaling and pharmacological mTOR inhibition. These findings reveal that neuronal mTOR signaling employs stimulus-specific combinations of dissociative protein interaction modules to encode opposing forms of synaptic plasticity.
The Microbiota-Derived Metabolite Deoxycholic Acid Regulates Enteric Neuron Activity and Connectivity.
Le Dréan ME, Ganachaud B, Rebion M … +8 more , Marchix J, Le Berre-Scoul C, Hulin P, Feyeux M, Talon S, Neunlist M, Caillaud M, Boudin H
J Neurochem · 2026 Jan · PMID 41532678 · Publisher ↗
Secondary bile acids (BAs) are metabolites produced by the gut microbiota and shown to impact digestive functions, at least in part through the enteric nervous system (ENS). In the ENS, enteric neurons express the BA rec...
Secondary bile acids (BAs) are metabolites produced by the gut microbiota and shown to impact digestive functions, at least in part through the enteric nervous system (ENS). In the ENS, enteric neurons express the BA receptor Takeda G protein-coupled receptor 5 (TGR5), making them potential direct cellular targets of secondary BAs, although their effects on enteric neuronal functions remain poorly understood. Enteric neuronal activity and connectivity form the basis of the regulatory control exerted by the ENS on gut functions. Yet, the influence of microbiota-derived metabolites, such as secondary BAs, on enteric neuron connectivity and synaptic activity remains largely unexplored. To address this question, we studied the effects of secondary BAs on neuronal connectivity using a model of rat primary culture of enteric neurons. We found that exposure to deoxycholic acid (DCA) increased the expression of key presynaptic proteins, synapsin-1 and synaptophysin, and enhanced synaptic density in enteric neurons. Moreover, DCA enhanced synaptic activity by increasing synaptic vesicle exocytosis upon KCl depolarisation, potentially through amplified phosphorylation of synapsin-1 at the Ser62-67 sites. In addition, we found that DCA modulated the intracellular Ca response induced by acetylcholine, a major excitatory neurotransmitter in enteric neurons, through a mechanism mediated by the TGR5 receptor. Overall, this study identifies DCA as a microbiota-derived compound capable of reshaping the enteric neuronal functional network. These findings highlight the potential of bacterial metabolites like DCA to link the microbiome with modulation of enteric neuronal activity and connectivity, supporting the relevance of secondary BAs in digestive physiology and their possible roles in gastrointestinal disorders.
Oxytocinergic Signaling in Zebrafish: Translational Perspectives for Autism Spectrum Disorder.
Peres G, Wiprich MT, Gusso D … +1 more , Bonan CD
J Neurochem · 2026 Jan · PMID 41527712 · Full text
Alterations in the oxytocin system, accompanied by cognitive and behavioral deficits, are common in several neurodevelopmental conditions, including Autism Spectrum Disorder. Oxytocin, a neuropeptide produced in the hypo...
Alterations in the oxytocin system, accompanied by cognitive and behavioral deficits, are common in several neurodevelopmental conditions, including Autism Spectrum Disorder. Oxytocin, a neuropeptide produced in the hypothalamus, plays a pivotal role in modulating social cognition and complex social behaviors. Recently, increasing attention has been given to the therapeutic potential of oxytocin in the treatment of neurodevelopmental disorders. However, many aspects of oxytocin signaling and its effects remain to be fully elucidated. Given its pronounced social behaviors and conserved neurochemical pathways, the zebrafish (Danio rerio) has emerged as a model for investigating the neural and behavioral effects of oxytocin. This species exhibits a wide behavioral repertoire, making it suitable for modeling oxytocin-related neurodevelopmental alterations. Here we provide an overview of the key mechanisms underlying oxytocin signaling and discuss current findings supporting the use of zebrafish as an Autism Spectrum Disorder model.
Cocaine-Induced Changes in the BRD4 Interactome Identifies Casein Kinase 1 Epsilon as a Therapeutic Target.
Seyednejad A, Sacko TJ, Babigian CJ … +4 more , Moore TE, Xiao S, Liddle JC, Sartor GC
J Neurochem · 2026 Jan · PMID 41521463 · Full text
Recent research has revealed that BRD4, a bromodomain and extra terminal domain (BET) epigenetic "reader" protein, plays an essential role in regulating behavioral and molecular responses to cocaine. To date, the roles o...
Recent research has revealed that BRD4, a bromodomain and extra terminal domain (BET) epigenetic "reader" protein, plays an essential role in regulating behavioral and molecular responses to cocaine. To date, the roles of BRD4 and other BET proteins in substance use disorder (SUD) models have been mainly studied using small molecule inhibitors that block the bromodomain interactions with acetylated histones. In other disease models, non-bromodomain BRD4-protein interactions have also been shown to play an important role in BRD4's molecular functions, but these interactions have yet to be studied in SUD models. Here, using BRD4 co-immunoprecipitation coupled to tandem mass spectrometry, we identified several putative BRD4-interacting proteins in the nucleus accumbens (NAc) that are altered by acute or repeated cocaine exposure in male and female Sprague Dawley rats. In BRD4-immunoprecipitated samples, gene ontology molecular function analysis revealed an enrichment of pathways associated with polymerase activity, SH3 domain binding, and chromatin-protein-adaptor activity in the cocaine treated groups. Notably, casein kinase 1 epsilon (CK1ε), a protein previously implicated in SUDs, was identified as a putative BRD4-interacting protein, and this association was increased following repeated cocaine injections. However, no significant change in total CK1ε protein expression was observed in the NAc via western blot following acute or repeated cocaine treatment. In additional experiments, we sought to determine the effects of CK1ε inhibition on the expression of a cocaine-related memory. Pharmacological inhibition of CK1ε with PF-4800567 diminished the expression of cocaine conditioned place preference. In a separate cohort of rats, an acute injection of PF-4800567 did not alter locomotor activity and anxiety-like behavior in the open field test. Collectively, these findings suggest that several novel proteins, including CK1ε, may play a role in BRD4-mediated molecular adaptations to cocaine exposure, and that CK1ε represents a potential target for future investigation in animal models of cocaine-seeking behavior.
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