Journal of Neurochemistry最新文献

{"title":"Aging Effects on Lipid Metabolism in Response to Traumatic Brain Injury","authors":"Regina F. Fernandez,&nbsp;Paulina Weglarczyk,&nbsp;Shaghayegh Zokaei,&nbsp;Suzette Huguenin,&nbsp;Joseph Scafidi,&nbsp;Jessica M. Ellis,&nbsp;Susanna Scafidi","doi":"10.1111/jnc.70227","DOIUrl":"https://doi.org/10.1111/jnc.70227","url":null,"abstract":"<p>Traumatic brain injury (TBI) is highly prevalent among very young and older adults, with poorer outcomes and longer recovery in aged individuals. The brain is a lipid-rich organ and high rates of membrane remodeling occur during recovery, yet remain poorly delineated, especially in aged. To determine the impact of age on lipid metabolism during TBI recovery, TBI was induced by control cortical impact in 3 (young) and 20 (aged) month-old mice. The ipsilateral cortex was harvested at 1-, 3-, 7-, and 28-day post injury (dpi) for analysis of gene expression, membrane lipidomics, total lipid fatty acid profile, and intermediates of fatty acid β-oxidation, acylcarnitines. Lipid metabolizing genes were largely downregulated in response to TBI in young mice, yet remained unchanged or were increased in aged mice, resulting in significantly higher expression in aged compared to young. TBI increased acylcarnitines by a robust ~3-fold in both young and aged cohorts acutely following injury and restored to sham levels by day 28. Phospholipidome compositional analysis reveals largest changes in the aged mice at 28 dpi. Aged mice phospholipid profiles shifted towards higher mono- and di- unsaturated and lower saturated and highly polyunsaturated species. Phospholipids with 4 unsaturated bonds, predicted to contain arachidonic acid, tended to increase post-TBI, whereas species containing 6 unsaturated bonds, predicted to contain docosahexaenoic acid (DHA) steadily declined during recovery. Total fatty acid analysis confirmed decreased DHA at 28 dpi in aged mice and more severely after TBI. In summary, TBI in aged led to a loss of transcriptional repression, more profound phospholipid change, earlier upregulation of acylcarnitines, and significant decrease in brain DHA content. Together, these data suggest that TBI occurrence in aging, compared to young, has less impact on gene expression of lipid metabolic genes but greater impact on lipid content.</p><p>\u0000 \u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure>\u0000 </p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 9","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.70227","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145038018","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nitration of Tyrosine Residue Y10 of Aβ1-42 Ameliorates Aβ1-42-Induced Neurotoxicity and Memory Impairment In Vitro and In Vivo","authors":"Jie Zhao,&nbsp;Jie Chen,&nbsp;Jing Lu,&nbsp;Qihui Shi,&nbsp;Qingyi Wang,&nbsp;Zhonghong Gao,&nbsp;Linghui Zeng,&nbsp;Qiong Liu","doi":"10.1111/jnc.70218","DOIUrl":"https://doi.org/10.1111/jnc.70218","url":null,"abstract":"<div>\u0000 \u0000 <p>The abnormal generation and aggregation of Aβ has been considered the central pathogenic mechanism of Alzheimer's disease (AD). Soluble Aβ tends to aggregate into toxic oligomers, which initiate neuronal dysfunction. Therefore, attenuation of Aβ oligomer formation might be an effective therapeutic strategy for AD. It has been reported that Aβ can be nitrated at tyrosine 10. Our previous study found that nitration of Y10 in Aβ significantly inhibits its aggregation and reduces its toxicity. However, the effects of Aβ nitration on its neurotoxicity remain unclear. Here, we used SH-SY5Y cells and a mouse model of AD induced by intrahippocampal Aβ_1-42 oligomer injection to investigate the effects of tyrosine nitration on the neurotoxicity of Aβ_1-42. The results of dot blot, gel electrophoresis analysis, transmission electron microscopy, atomic force microscopy, and dynamic light scattering indicated that nitration of Y10 in Aβ_1-42 inhibits its oligomerization. Aβ_1-42 treatment perturbed the integrity of intracellular membranes, eventually leading to apoptosis of SH-SY5Y cells. In contrast, nitrated Aβ_1-42 exhibited little neurotoxicity toward SH-SY5Y cells. Additionally, mice injected with Aβ_1-42 oligomer developed cognitive impairment in behavioral tests. Aβ_1-42 oligomer caused neurotoxicity in the hippocampus of the mice, possibly through triggering apoptosis and neuroinflammation and promoting aberrant amyloid processing. As expected, nitrated Aβ_1-42 also had little effect on physiological and cognitive capacities. These results further confirm that nitration of Y10 in Aβ can significantly inhibit its neurotoxicity. Moreover, our findings contribute to the understanding of the role of Aβ in the development of AD.</p>\u0000 <p>\u0000 \u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure>\u0000 </p>\u0000 </div>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 9","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145038048","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"14-3-3 Proteins Negatively Regulate Microglial Activation via Inhibition of the NF-κB Pathway","authors":"William J. Stone,&nbsp;Frank Sanders Pair,&nbsp;Roschongporn Ekkatine,&nbsp;Mary Gannon,&nbsp;Kasandra Scholz,&nbsp;Rudradip Pattanayak,&nbsp;Rohma Syed,&nbsp;Talene A. Yacoubian","doi":"10.1111/jnc.70228","DOIUrl":"10.1111/jnc.70228","url":null,"abstract":"<div>\u0000 \u0000 <p>Microglia, the resident immune cells of the central nervous system (CNS), are involved in the pathogenesis of neurodegenerative diseases, such as Alzheimer's disease (AD), Dementia with Lewy Bodies (DLB), and Parkinson's disease (PD). 14-3-3 proteins act as molecular hubs to regulate protein–protein interactions, which are involved in numerous cellular functions, including cellular signaling, protein folding, and apoptosis. We previously revealed decreased 14-3-3 levels in the brains of human subjects with neurodegenerative diseases. In this study, we examined the role of 14-3-3 proteins in the microglial proinflammatory response to lipopolysaccharide (LPS). We found that LPS treatment induced 14-3-3 protein levels within 6 hours. With the use of BV02 and dimeric fourteen-three-three peptide inhibitor (difopein), a small molecule and peptide inhibitor of 14-3-3 protein–protein interactions, respectively, we found a dramatic increase in microglial activation markers in both immortalized BV-2 microglial cells and in primary mouse microglia. Both 14-3-3 inhibitors also increased LPS-induced microglial phagocytosis, lysosomal proteolysis, and cytokine release in primary microglia. In contrast, chemotaxis toward the cellular damage stimulus, adenosine triphosphate (ATP), was diminished with 14-3-3 inhibition. Inhibition of 14-3-3's hastened LPS-induced activation of the nuclear factor-kB (NF-κB) signaling pathway, as measured by its nuclear translocation. 14-3-3's reduced activation of the NF-κB pathway by binding and inhibiting the release of IκB kinase beta (IKKβ). Disruption of 14-3-3's binding to IKKβ with BV02 or difopein increased the downstream phosphorylation and degradation of the inhibitor of NF-κB alpha (IκBα). Collectively, our findings suggest 14-3-3 proteins play a critical role in the regulation of inflammatory responses in microglia and may serve as potential targets for immunotherapy of CNS diseases.</p>\u0000 <p>\u0000 \u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure>\u0000 </p>\u0000 </div>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 9","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145033558","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Neuropathology of Alcohol Use Disorder: Cellular Insights From Human Post-Mortem Studies","authors":"Ameer E. Rasool,&nbsp;Jennifer L. Cornish,&nbsp;Asheeta A. Prasad","doi":"10.1111/jnc.70233","DOIUrl":"10.1111/jnc.70233","url":null,"abstract":"<p>Alcohol use disorder (AUD) is a complex neurological disorder with limited treatments available. Thus, understanding the neurobiological changes associated with AUD is crucial for the development of effective therapeutic approaches. Analysis of human post-mortem tissue provides insight into the long-term effects of alcohol use and cellular changes that contribute to addiction behavior. Here, we provide a collection of cellular changes found in human AUD post-mortem brain tissue, revealing brain region-specific cellular adaptations that map a complex neurobiological landscape of addiction. Examination across the cortex, striatum, hippocampus, hypothalamus, cerebellum, and midbrain reveals that although degeneration, metabolic disruption, and neuroinflammatory processes are common cellular processes that are impacted, these changes are distinctive by brain region and cell type. For example, white matter loss dominates in the prefrontal cortex, the hippocampus is sensitive to glial cell loss, subtypes of hypothalamic neurons are disproportionately affected, and the striatum shows subregional changes. Although these cellular adaptations are brain region and cell type specific, this review of studies over the last 30 years suggests that neuropathology in AUD undergoes neural network reorganization. Whether these changes are a response to chronic alcohol use or underlying alcohol-seeking behavior is a limitation of post-mortem analysis. However, mechanistic studies of rodent models and convergent evidence from human post-mortem tissue have identified therapeutic candidates such as oxytocin and GLP-1. Insights from animal studies have also highlighted underexplored yet potentially pivotal regions in AUD, such as the anterior insular cortex and the ventral pallidum, in human studies. Other limitations include a lack of sex-specific analyses, the incorporation of advanced neuroscience tools, and multiple regional analyses. Integrating AUD human post-mortem tissue bridges preclinical and clinical research, providing an invaluable understanding of neural mechanisms underpinning AUD and potential avenues for targeted interventions.</p><p>\u0000 \u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure>\u0000 </p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 9","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.70233","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145033523","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Presynaptic ATP Decreases During Physiological-Like Activity in Neurons Tuned for High-Frequency Transmission","authors":"Isabelle Straub,&nbsp;Lukas Kunstmann,&nbsp;Felipe Baeza-Lehnert,&nbsp;Saad Chowdhry,&nbsp;Robert B. Renden,&nbsp;Gerardo Gonzalez-Aragón,&nbsp;Bernhard Groschup,&nbsp;Thomas Hofmann,&nbsp;Saša Jovanović,&nbsp;Mandy Sonntag,&nbsp;Daniel Gitler,&nbsp;Michael Schaefer,&nbsp;Jens Eilers,&nbsp;L. Felipe Barros,&nbsp;Johannes Hirrlinger,&nbsp;Stefan Hallermann","doi":"10.1111/jnc.70212","DOIUrl":"https://doi.org/10.1111/jnc.70212","url":null,"abstract":"<p>Recent evidence indicates that the concentration of ATP remains stable during neuronal activity due to activity-dependent ATP production. However, the mechanisms of activity-dependent ATP production remain controversial. To stabilize the ATP concentration, feedforward mechanisms, which may rely on calcium or the sodium-potassium pump, do not require changes in the ATP and ADP concentrations. On the other hand, feedback mechanisms could be triggered by changes in the concentration of the adenine nucleotides. To test the possibility of feedback mechanisms, we quantified the ATP concentration in presynaptic terminals during synaptic activity in acute brain slices from mice stably expressing a genetically encoded ATP sensor. We first focused on the cerebellar mossy fiber bouton (cMFB) as a large presynaptic terminal that is specialized for high-frequency synaptic transmission. At physiological temperature and metabolite concentrations, the resting ATP concentration was in the range of approximately 2.5–2.7 mM. During strong, presumably non-physiological activity, the ATP concentration decreased within a few seconds. Experiments with blockade of ATP production indicated that ATP production increased ~10-fold during neuronal activity. Weaker stimulation resembling physiological activity at this synapse caused a decrease in ATP concentration by ~150 μM. We found similar results with in vivo-recorded spike sequences at the calyx of Held, another central glutamatergic synapse tuned for high-frequency synaptic activity. At conventional small synapses of cultured hippocampal neurons, weak stimulations also caused a decrease in ATP concentrations. Finally, quantitative modeling indicated that a pure ADP-based feedback mechanism can explain the activity-dependent ATP production when assuming a three-times higher maximal rate of ATP production compared to our measured rate of ATP production during high-frequency transmission. Our data reveal ATP reduction in presynaptic terminals during physiological-like activity, provide quantitative constraints on feedback mechanisms, and suggest that the ATP concentration can decrease during signaling, at least in some neuronal compartments of our brain.</p><p>\u0000 \u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure>\u0000 </p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 9","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.70212","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145012863","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Peripheral Inflammation Is Associated With Greater Neuronal Injury and Lower Episodic Memory Among Late Middle-Aged Adults","authors":"Mona-Lisa Malarte,&nbsp;Konstantinos Chiotis,&nbsp;Konstantinos Ioannou,&nbsp;Elena Rodriguez-Vieitez","doi":"10.1111/jnc.70222","DOIUrl":"https://doi.org/10.1111/jnc.70222","url":null,"abstract":"<p>Elucidating the earliest biological mechanisms underlying Alzheimer's disease (AD) is critical for advancing early detection strategies. While amyloid-β (Aβ) and tau pathologies have been central to preclinical AD research, the roles of peripheral biological processes in disease initiation remain underexplored. We investigated patterns of ¹⁸F-MK6240 tau positron emission tomography (PET) and peripheral inflammation across stages defined by Aβ burden and neuronal injury in <i>n</i> = 132 (64.5 ± 3.4 years old, 69.7% female, 10.7 ± 4.0 years of education, 34.1% APOE4 carriers) cognitively unimpaired late middle-aged Hispanic adults. ¹⁸F-MK6240 tau PET imaging revealed early entorhinal and neocortical tau deposition even in individuals lacking biomarker evidence of neuronal injury as measured by plasma neurofilament light (NfL). Peripheral inflammatory markers were not directly associated with Aβ or tau load but exhibited robust associations with neuronal injury (plasma NfL). Importantly, the hallmark biomarkers of AD proteinopathy (Aβ and tau) did not show a significant association with episodic memory performance, whereas peripheral inflammation and plasma NfL markers demonstrated links to subtle episodic memory impairment. Furthermore, Aβ and tau deposition appeared primarily influenced by genetic predisposition and sex, whereas peripheral inflammation was strongly associated with both neuronal injury (plasma NfL) and comorbidities including higher Body Mass Index (BMI) and Diabetes Mellitus (DM). These findings reveal a complex interplay between central and peripheral mechanisms in the potential earliest phases of AD pathophysiology and argue for the integration of peripheral inflammatory and neurodegeneration markers into models of preclinical AD progression. Recognizing the heterogeneity of early biological changes could refine risk stratification, biomarker development, and preventative strategies targeting inflammation and vascular health in cognitively unimpaired individuals at risk for AD.</p><p>\u0000 \u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure>\u0000 </p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 9","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.70222","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145012865","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Acetylation Mimetic and Null Mutations Within the Filament Core of P301L Tau Have Varied Effects on Susceptibility to Seeding and Aggregation","authors":"Ethan D. Smith,&nbsp;Jose Torrellas,&nbsp;Robert McKenna,&nbsp;Quan Vo,&nbsp;Mario Mietzsch,&nbsp;David R. Borchelt,&nbsp;Stefan Prokop,&nbsp;Paramita Chakrabarty","doi":"10.1111/jnc.70221","DOIUrl":"https://doi.org/10.1111/jnc.70221","url":null,"abstract":"<div>\u0000 \u0000 <p>The two most prominent post-translational modifications of pathologic tau are Ser/Thr/Tyr phosphorylation and Lys acetylation. Whether acetylation impacts the susceptibility of tau to templated seeding in diseases like Alzheimer's disease (AD) and Progressive Supranuclear Palsy (PSP) is largely uncharacterized. Towards this, we examined how acetylation mimicking or nullifying mutations on five sites of tau (K311, K353, K369, K370, K375), located within the tau filament core, influenced the susceptibility of P301L (PL) tau to seeds from AD (AD-tau) or PSP (PSP-tau) brain donors in HEK293T cells. Acetyl-mimicking substitutions of individual Lys sites to Glutamine as well as mutation of all 5 sites together (PL+5K-Q and PL+5K-R) had inconsistent effects on tau seeding by AD-tau or PSP-tau seeds. Unexpectedly, mutating all 5 sites to Alanine (PL+5K-A) resulted in a tau variant that spontaneously aggregated. These aggregates were amorphous and yet able to propagate to naïve cells expressing P301L tau but not wild-type tau. Previously, we reported that a phospho-mimetic S305E mutation in PL tau abrogated seeding by AD-tau but not PSP-tau seeds in the HEK293T cells. To assess how changes in acetylation and phosphorylation together could influence seeding, we combined the S305E and the 5K-Q mutations in PL tau, creating a variant that retained specificity for PSP-tau seeds over AD-tau seeds. Our findings indicate that phosphorylation of tau at Ser305 is a strong determinant of disease-specific tau templating, even in the presence of hyperacetylation within the fibril core domain. Overall, our findings suggest that acetylation in the tau filament core domain has limited effects on tau seeding.</p>\u0000 <p>\u0000 \u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure>\u0000 </p>\u0000 </div>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 9","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145012864","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of CPEBs in Learning and Memory","authors":"David A. Hicks,&nbsp;Liam D. Aubrey,&nbsp;Jessica C. F. Kwok,&nbsp;Sheena E. Radford","doi":"10.1111/jnc.70226","DOIUrl":"https://doi.org/10.1111/jnc.70226","url":null,"abstract":"<p>Memory formation involves a complex interplay of molecular and cellular processes, including synaptic plasticity mechanisms such as long-term potentiation (LTP) and long-term depression (LTD). These processes rely on activity-dependent gene expression and local protein synthesis at synapses. A central unresolved question in neuroscience is how memories can be stably maintained over time, despite the transient nature of the proteins involved in their initial encoding. A key candidate addressing this ‘maintenance paradox’ is the CPEB (cytoplasmic polyadenylation element-binding protein) family, particularly CPEB3. CPEBs are RNA-binding proteins that regulate the polyadenylation and translation of dormant mRNAs, enabling synaptic tagging and memory consolidation. CPEB3 has been shown to modulate the expression of critical synaptic proteins, including AMPA and NMDA receptor subunits, thereby influencing synaptic strength and long-term memory persistence. Structurally, CPEB3 features a disordered N-terminal domain (NTD) enriched in glutamine and proline residues, which may facilitate reversible aggregation and phase separation and an actin-binding domain, potentially supporting its localisation to ribonucleoprotein granules. The highly conserved C-terminal domain (CTD) contains RNA-recognition motifs essential for mRNA binding. Together, these structural features may enable CPEB3 to function as a molecular switch, linking synaptic activity to enduring changes in protein synthesis and memory encoding. Here, we review the current understanding of the function of CPEB3, highlighting current hypotheses and debates of the role(s) of protein self-assembly in memory formation.</p><p>\u0000 \u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure>\u0000 </p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 9","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.70226","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145012475","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Central Neurophysiological Alterations in Dystrophic mdx Mice Correlate With Reduced Hippocampal Levels of the Endogenous NMDA Receptor Ligand D-Aspartate","authors":"Francesca Mastrostefano,&nbsp;Martina Garofalo,&nbsp;Tommaso Nuzzo,&nbsp;Claudio Bruno,&nbsp;Francesco Errico,&nbsp;Alessandro Usiello,&nbsp;Maria Egle De Stefano","doi":"10.1111/jnc.70223","DOIUrl":"https://doi.org/10.1111/jnc.70223","url":null,"abstract":"<p>Patients with Duchenne muscular dystrophy (DMD) may experience neurobehavioral and cognitive concerns, including psychiatric symptoms, due to the absence of full-length dystrophin (Dp427), frequently accompanied by deficiencies in shorter isoforms. The lack of dystrophin affects neurophysiological processes from the uterine phase, impacting neural circuitry in brain regions such as the prefrontal cortex, hippocampus, and cerebellum. This leads to reduced inhibitory GABAergic transmission and altered hippocampal glutamatergic signaling. The resulting imbalance between inhibitory and excitatory inputs contributes to the neurodevelopmental and cognitive deficits observed in DMD. Recent studies have reported correlations between serum levels of D-aspartate and D-serine, endogenous ligands of glutamatergic receptors, and conditions such as schizophrenia, spinal muscular atrophy, and aging. Furthermore, in a recent clinical study, we reported a general dysregulation of D−/L-amino acids known to modulate glutamatergic neurotransmission in the serum of DMD patients, with significant correlations between muscle wasting, motor impairment, and alterations in L-glutamate levels and the L-glutamine/L-glutamate ratio. To delve deeper into this matter, we conducted an extensive neurochemical analysis using high-pressure liquid chromatography to measure the levels of the same D−/L-amino acids across various brain regions, the spinal cord, and serum of the <i>mdx</i> mouse model of DMD. Our results revealed a significant reduction in prenatal D-aspartate levels and postnatal levels of specific L-amino acids in the hippocampus of dystrophic mice compared to wild type. In adult <i>mdx</i> mice, we also observed a near-significant decrease in hippocampal D-serine levels and a significant reduction in spinal cord D-aspartate levels. This study provides the first evidence potentially linking D-/L-amino acid dysmetabolism in the hippocampus to the described neurophysiological alterations. Although further investigations are essential to validate this hypothesis, the mechanisms proposed here offer insight into how amino acid imbalances may contribute to the DMD-associated neurological and cognitive deficits, thus supporting the rationale for developing future targeted therapeutic strategies.</p><p>\u0000 \u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure>\u0000 </p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 9","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.70223","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144999055","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Alternative Splicing of the NMDA Receptor Subunit GluN1 Mediated by Polypyrimidine Tract-Binding Protein Dimerization in the Trigeminal Ganglion Contributes to Orofacial Allodynia","authors":"Yi-Ke Li,&nbsp;Ya-Jing Liu,&nbsp;Yan-Yan Zhang,&nbsp;Yue-Ling Li,&nbsp;Chen Li,&nbsp;Qin-Xuan Song,&nbsp;Cheng Zhou,&nbsp;Fei Liu,&nbsp;Jie-Fei Shen","doi":"10.1111/jnc.70220","DOIUrl":"https://doi.org/10.1111/jnc.70220","url":null,"abstract":"<div>\u0000 \u0000 <p>Orofacial neuropathic pain, a debilitating condition associated with trigeminal nerve injury, is often characterized by allodynia. <i>N</i>-methyl-<span>d</span>-aspartate receptors (NMDARs), particularly the GluN1 subunit, play a central role in mediating this pain. The GluN1 subunit undergoes alternative splicing at exon 5, generating isoforms GluN1a (lacking the exon 5-encoded N1 cassette) and GluN1b (retaining the N1 cassette), which have distinct functional roles. However, the contribution of GluN1 exon 5 splicing and the mechanisms governing this process in orofacial neuropathic pain are not fully understood. This study investigates the role of GluN1 exon 5 splicing in the development of orofacial allodynia utilizing a mouse model of chronic constriction injury of the infraorbital nerve (CCI-ION). We found that CCI-ION induces enhanced exon 5 splicing in the trigeminal ganglion (TG), promoting the expression of GluN1a and contributing to orofacial allodynia. A key regulator of this splicing event is the polypyrimidine tract-binding protein (PTB), which binds to GluN1 pre-mRNA in a manner dependent on PTB dimerization. We also identified protein disulfide isomerase 3 (PDIA3) as a modulator of PTB dimerization. PDIA3 regulates the formation of PTB dimers in the nucleus, which drives GluN1 exon 5 splicing and the development of orofacial allodynia. These findings reveal a PDIA3-PTB-GluN1 axis that regulates alternative splicing of GluN1 exon 5 in response to trigeminal nerve injury, providing new insights into the molecular mechanisms underlying orofacial neuropathic pain and potential therapeutic targets for its treatment.</p>\u0000 <p>\u0000 \u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure>\u0000 </p>\u0000 </div>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 9","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144998615","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}