Journal of Neurochemistry最新文献

{"title":"Extracellular Vesicle-Derived microRNAs as Fluid Biomarkers in Neurodegenerative Diseases: A Systematic Review","authors":"Aliyah Zaman,&nbsp;Sienna S. Drake,&nbsp;Alyson E. Fournier","doi":"10.1111/jnc.70323","DOIUrl":"10.1111/jnc.70323","url":null,"abstract":"<p>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.</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":"170 1","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12828110/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146030061","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":"Alterations in Both Caliber and Myelination of Callosal Axons Elicited by Ubiquitous Genetic Ablation of c-Jun Amino-Terminal Kinase 3 (JNK3)","authors":"Costanza Ferrari Bardile,&nbsp;Mercedes Priego,&nbsp;Harwin Sidik,&nbsp;Vincent Tano,&nbsp;Sarah R. Langley,&nbsp;Mahmoud A. Pouladi,&nbsp;Gerardo Morfini","doi":"10.1111/jnc.70356","DOIUrl":"10.1111/jnc.70356","url":null,"abstract":"<div>\u0000 \u0000 <p>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.</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":"170 1","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146018862","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":"Prosaposin Is Cleaved Into Saposins by Multiple Cathepsins in a Progranulin-Regulated Fashion","authors":"Molly Hodul,&nbsp;Courtney Lane-Donovan,&nbsp;Emily S. Cheang,&nbsp;Vienna Gao,&nbsp;Paul J. Sampognaro,&nbsp;Edwina A. Mambou,&nbsp;Zoe Yang,&nbsp;Aimee W. Kao","doi":"10.1111/jnc.70357","DOIUrl":"10.1111/jnc.70357","url":null,"abstract":"<p>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.</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":"170 1","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12828107/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146029996","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":"TFG p.G269V Mutation Disrupts Motor Neuron Function in iPSC-Derived Models via Wnt Signaling Dysregulation","authors":"Zhiqiang Mu,&nbsp;Jielin Wang,&nbsp;Tian Xiao,&nbsp;Kun Chen,&nbsp;Xinyu Chen,&nbsp;Qiurong Liu,&nbsp;Jiahui Huang,&nbsp;Yuanbo Li,&nbsp;Jing Chen,&nbsp;Yuanming Wu,&nbsp;Fangfang Liu","doi":"10.1111/jnc.70359","DOIUrl":"10.1111/jnc.70359","url":null,"abstract":"<div>\u0000 \u0000 <p>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 (<i>TFG</i>) 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.</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":"170 1","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146030067","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":"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”","authors":"","doi":"10.1111/jnc.70354","DOIUrl":"10.1111/jnc.70354","url":null,"abstract":"<p>Miya, K., K. Ohta, K. Keino-Masu, et al. 2026. “Essential Roles of Heparan Sulfate Endosulfatase Sulf1 in Reward and Aversion Learning Through Distinct Dopamine D1 and D2 Receptor Pathways in Male Mice.” <i>Journal of Neurochemistry</i> 170: e70338. https://onlinelibrary.wiley.com/doi/10.1111/jnc.70338.</p><p>In paragraph 3 of the “Introduction” section, the text “Vieitas-Gapar et al., 2025” was incorrect.</p><p>This should have read as follows: “Vieitas-Gaspar et al., 2025.”</p><p>In “Primer name” of TABLE 1, the text “Drd1a F1 (#)” was incorrect.</p><p>This should have read as follows: “Drd1a F1 (#7).”</p><p>In “Sample size” for Figure 6a of TABLE 2, the text “D2cKO, <i>n</i> = 6” was incorrect.</p><p>This should have read as follows: “D1cKO, <i>n</i> = 6.”</p><p>In the “References” section, “Miya, K., E. Suzuki, K. Keino-Masu, et al. 2025. “Altered Excitability and Glutamatergic Synaptic Transmission in the Medium Spiny Neurons of the Nucleus Accumbens in Mice Deficient in the Heparan Sulfate Endosulfatase Sulf1.” <i>eNeuro</i>. https://doi.org/10.1523/ENEURO.0088-25.2025.” was incorrect.</p><p>This should have read as follows: “Miya, K., E. Suzuki, K. Keino-Masu, et al. 2025. “Altered Excitability and Glutamatergic Synaptic Transmission in the Medium Spiny Neurons of the Nucleus Accumbens in Mice Deficient in the Heparan Sulfate Endosulfatase Sulf1.” <i>eNeuro</i> 13(1) ENEURO.0088-25.2025.”</p><p>We apologize for this error.</p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"170 1","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.70354","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146010808","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":"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","authors":"An Wang,&nbsp;Hong-fei Tai,&nbsp;Kang Zhang,&nbsp;Yi Zhou,&nbsp;Wei Sun,&nbsp;Zheng-guang Guo,&nbsp;Hai-dan Sun,&nbsp;Fan Jian,&nbsp;Xin-gao Wang,&nbsp;Hua Pan,&nbsp;Zai-qiang Zhang","doi":"10.1111/jnc.70352","DOIUrl":"10.1111/jnc.70352","url":null,"abstract":"<div>\u0000 \u0000 <p>Neuronal Intranuclear Inclusion Disease (NIID), caused by GGC repeat expansions in the <i>NOTCH2NLC</i> 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.</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":"170 1","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146010728","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":"Sevoflurane Inhibits Layer 5 Pyramidal Neurons via Kv1.2-Dependent Modulation of Subthreshold Currents","authors":"Aelton S. Araujo,&nbsp;Gabriel M. de Queiroz,&nbsp;Sérgio Ruschi B. Silva,&nbsp;Werner Treptow,&nbsp;Katarina E. Leao","doi":"10.1111/jnc.70360","DOIUrl":"10.1111/jnc.70360","url":null,"abstract":"<p>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.</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":"170 1","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12817328/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146010771","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":"Isoform-Specific Splicing of ANK2 by PTBP2 Orchestrates Retinal Pigment Epithelial-to-Neuron Fate Conversion","authors":"Yun-Xi Ma,&nbsp;Yan-Ke Zhang,&nbsp;Jun Li,&nbsp;Bing-Lin Zhu","doi":"10.1111/jnc.70358","DOIUrl":"10.1111/jnc.70358","url":null,"abstract":"<div>\u0000 \u0000 <p>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 <i>PTBP2</i> and the barrier protein <i>p53</i> 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 <i>PTBP2</i> depletion induces widespread AS changes, most notably promoting near-complete inclusion of exon 36 in the <i>ANK2</i> 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 <i>ANK2</i> 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 <i>PTBP2</i>-<i>ANK2</i> 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.</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":"170 1","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146003724","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":"Oxidative Stress—Related Serum Extracellular Vesicle miRNAs Indicate Symptom Severity and Cognitive Decline in Parkinson's Disease","authors":"Violeta Belickienė,&nbsp;Aistė Pranckevičienė,&nbsp;Andrius Radžiūnas,&nbsp;Andrėja Strigauskaitė,&nbsp;Ovidijus Laucius,&nbsp;Paulina Vaitkienė","doi":"10.1111/jnc.70355","DOIUrl":"10.1111/jnc.70355","url":null,"abstract":"<p>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.</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":"170 1","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.70355","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145998557","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":"Dissociation of the mTOR Protein Interaction Network Following Neuronal Activation Is Altered by Shank3 Mutation","authors":"Devin T. Wehle,&nbsp;Emily A. Brown,&nbsp;Vera Stamenkovic,&nbsp;Breann Gniffen,&nbsp;Felicia M. Harsh,&nbsp;Stephen E. P. Smith","doi":"10.1111/jnc.70353","DOIUrl":"10.1111/jnc.70353","url":null,"abstract":"<p>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.</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":"170 1","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12802388/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145965709","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}