Journal of Neurochemistry最新文献

Epileptogenesis involves widespread molecular remodeling, including transcriptional and post-transcriptional changes that reshape neuronal networks. While microRNAs have been extensively studied in this context, the contribution of transfer RNA-derived small RNAs (tsRNAs) remains largely unexplored. Understanding how tsRNAs engage in Argonaute 2 (Ago2)-mediated regulation during epileptogenesis could uncover new layers of post-transcriptional control relevant to seizure development and progression. Recent studies increasingly recognize transfer RNA-derived small RNAs or tsRNAs, especially those bound to Argonaute 2 (Ago2), as functional regulators of gene expression. Here, we analyzed Ago2-immunoprecipitated small RNA-Seq data along with matching transcriptomic and proteomic data across seven defined timepoints in a rat model of epilepsy that was induced using perforant pathway stimulation (PPS). The analysis showed dynamic shifts in Ago-2 bound tsRNA expression, with early and intermediate stages showing upregulation of shorter tsRNA fragments, whereas Day of First Seizure (DOFS) and chronic timepoints showed a shift toward 5′ tiRNAs, including highly upregulated GlyGCC-derived fragments. Cluster analysis using Weighted Gene Co-Expression Network Analysis (WGCNA) identified modules specific to the DOFS timepoint where tsRNAs clustered together with genes enriched in pathways including neuronal metabolism, mitochondrial function, and synaptic stability. Target prediction analysis using RNAhybrid at DOFS predicted targets in 3′ UTR, 5′ UTR, and CDS regions showing an association with glycolysis, protein localization, and vesicle trafficking. Subsequent gene-disease association analysis further associated the predicted targets with neurodegenerative conditions including but not limited to Alzheimer's disease, intellectual disability, and epilepsy. This study highlights that tsRNAs potentially play a temporal dynamic regulatory role in epileptogenesis with an evident shift in tsRNA accumulation at DOFS suggesting a potential rewiring of post-transcriptional control at the completion of epileptogenesis. This work also highlights a first integrative approach of tsRNA downstream effects on the transcriptome and proteome in epilepsy and suggests innovative tsRNA-driven mechanisms relevant to disease progression.

Oligodendrocytes, traditionally recognized for their role in axonal myelination, are increasingly appreciated as metabolically dynamic and functionally diverse cells integral to central nervous system (CNS) homeostasis. This review delineates the evolving neurochemical landscape of oligodendrocyte physiology, emphasizing their roles beyond myelin production. We explore key processes including lipid metabolism, metabolic coupling with neurons, ion buffering, neurotransmitter signaling, and synaptic modulation. Oligodendrocytes preferentially utilize aerobic glycolysis and support axonal energy metabolism via the export of lactate and phosphocreatine, maintaining ATP levels even in the absence of mitochondria within the myelin sheath. Their capacity for regional and transcriptional heterogeneity allows adaptive responses to local microenvironments and neuronal activity. Lipid biosynthesis and storage mechanisms are intricately regulated through mTORC1, SREBPs, and lipophagy, enabling rapid membrane expansion, and structural integrity during myelination. Furthermore, oligodendrocytes modulate the periaxonal milieu via potassium buffering, pH regulation, and osmotic balance, primarily through Kir channels, carbonic anhydrases, and aquaporins. They also express a wide array of neurotransmitter receptors, enabling bidirectional communication with neurons and activity-dependent modulation of maturation and plasticity. Intracellular signaling pathways such as PI3K/Akt/mTOR, MAPK/ERK, and Wnt/β-catenin orchestrate the integration of metabolic and transcriptional programs. Collectively, these findings redefine oligodendrocytes as active participants in CNS physiology, contributing to neuronal health, circuit plasticity, and responses to injury or disease.

Glial cell line-derived neurotrophic factor (GDNF) has been investigated as a therapeutic agent for Parkinson's disease (PD), albeit with variable clinical outcomes. In the brain, GDNF is predominantly produced by striatal interneurons. Given that Gdnf gene expression is regulated by cyclic adenosine monophosphate (cAMP)-dependent signaling, a compelling strategy for PD treatment is the pharmacological elevation of intracellular cAMP. This approach aims to enhance endogenous GDNF, offering potential neuroprotective benefits. In this study, we show that selective inhibition of phosphodiesterases (PDEs) subtypes, therefore enhancing intracellular cAMP levels, increases Gdnf mRNA expression in striatal slices ex vivo; however, achieving this effect in vivo proved more challenging. To address this, we evaluated Ibudilast, a clinically approved non-selective PDE inhibitor. Ibudilast robustly upregulated striatal Gdnf expression both ex vivo and in vivo following systemic administration. In a chronic MPTP mouse model of PD, Ibudilast treatment conferred significant neuroprotection, as evidenced by preservation of tyrosine hydroxylase-positive (TH+) neurons in the substantia nigra, attenuation of TH+ fiber loss in the striatum, and mitigation of striatal dopamine depletion. Given its established clinical use and favorable safety profile, these findings support further investigation of Ibudilast as a potential disease-modifying therapy in PD.

Within the emerging field of spatial biology, novel analytical technologies are increasingly demonstrated for mapping neurochemical changes in situ. These tools comprise spatial mass spectrometry (MS imaging, MSI), spatial transcriptomics using in situ sequencing, probe-based spatial omics, as well as laser microdissection and single cell-type isolation interfaced with either mass spectrometry or next generation RNA sequencing (NGS) for single cell-type analysis. These approaches significantly exceed the neurochemical methods that are commonly used with respect to molecular specificity and spatial precision. However, despite all these advancements, close attention has still to be paid to appropriate tissue harvesting and enzyme inactivation methods to avoid degradation of neurochemicals and the generation of artifacts, and because of euthanasia or postmortem ischemia. In this editorial, we aim to present the readership with considerations in lieu of emerging analytical and spatial molecular techniques, as well as highlight the relevance of appropriate tissue preparation. Importantly, we discuss different quenching techniques and their compatibility as well as limitations for novel spatial analyses that require morphologically pristine tissues.

Type 2 diabetes mellitus (T2DM) is associated with poorer cognitive performance and increased dementia risk. Pathophysiological mechanisms are not fully understood. In this prospective study of UK Biobank participants, (n = 9943 without T2DM, age = 56.3 ± 8.2 years, 55% female, n = 3752 with T2DM, age = 59.1 ± 7.7 years, 41% female), T2DM was associated with poorer attention (Hedges' g = −0.15[−0.17, −0.10]), processing speed (Hedges' g = −0.14[−0.17, −0.09]), and a higher risk of incident dementia over 15 years (HR = 2.13[1.74, 2.61]). Among 2923 proteins measured by Olink proteomics, 1739 were differentially expressed in T2DM. Four-way decomposition models of proteomic markers, and KEGG pathway analyses, were used to identify potential mediating and moderating effects of biological pathways on the association between T2DM and cognitive or dementia outcomes. For dementia, 230 protein mediators implicated inflammatory pathways (complement/coagulation cascades, cytokine-cytokine receptor interactions, and the janus kinase-signal transducer and activator of transcription signaling pathway), and 11 proteins implicated cholesterol/lipid metabolism as moderators (including apolipoprotein E, low-density lipoprotein receptor and prostaglandin reductase 1). Mediators with the highest accuracy to predict incident dementia in T2DM were glial fibrillary acidic protein (AUC = 0.71[0.67, 0.76]) and neurofilament light polypeptide (AUC = 0.71 [0.67, 0.75]). Multivariate proteomic/clinical models (AUC = 0.78 [0.75, 0.81]) improved accuracy beyond clinical risk factors alone (AUC = 0.74 [0.69, 0.78]). Subgroup analyses by sex, apolipoprotein E ε4 carrier status and age showed some features unique within strata. This study suggests potential targets within inflammatory, oxidative, angiogenesis-related, and metabolic pathways to mitigate cognitive decline and dementia risk in T2DM.

Plasma biomarkers have emerged as promising less invasive alternatives for Alzheimer's disease (AD) detection. However, the diagnostic performance of phosphorylated tau (p-tau) isoforms remains incompletely validated. In a cohort of 160 patients from a memory clinic, plasma levels of p-tau217, p-tau212, p-tau181, p-tau231, and BD-tau were measured using Single Molecule Array (Simoa) in-house assays, alongside NFL and GFAP. Subjects were classified using the Erlangen Score into Controls (n = 53), neurochemically possible AD (n = 27), and probable AD (n = 80). Plasma concentrations of all p-tau isoforms were significantly elevated in both Possible AD and Probable AD groups compared to Controls (p < 0.001). Notably, p-tau217 exhibited the highest diagnostic accuracy (AUC = 0.954) and correlated with CSF classical biomarkers. A positive result for p-tau217 increases the probability of AD almost fivefold. Plasma p-tau217 reflects AD neurochemical changes and has high negative predictive value, supporting its use as a screening tool. However, moderate PPV suggests the need for confirmatory testing to ensure an accurate diagnosis.

Genetic variants in the X-chromosomal gene coding for the calcium−/calmodulin-dependent serine protein kinase (CASK) are associated with a neurodevelopmental disorder. CASK is a member of the membrane-associated guanylate kinase (MAGUK) family of proteins. It acts as a scaffold at presynaptic sites, as a regulator of the transport of glutamate receptors, and as a transcriptional regulator. The PDZ domain of CASK has been reported to bind to presynaptic cell adhesion molecules such as Neurexin1-3, CNTNAP2, SynCAM and SALM1. Structural analyses of related MAGUKs indicate that the canonical SH3 and GK domains combine with the PDZ domain to form the so-called PSG supramodule. Conserved aromatic residues (Y723 and W914) flanking the GK domain contribute to the formation of a dimeric structure of two PSG modules, which is required for high-affinity binding to the type 2 PDZ ligand motif of, for example, Neurexin. Here we identify previously uncharacterized patient variants in the SH3 domain of CASK (I672V; P673L), which alter the intermolecular binding pocket for Y723. Both variants interfere with the binding of Neurexin-1β, in a manner similar to the previously reported Y723C variant. Intriguingly, binding to the type 1 PDZ ligand of the cell adhesion molecule SALM1 is not altered. Using a set of highly selective patient variants, we show that the binding of SALM1 to CASK is actually not mediated by the CASK PDZ domain or the PSG supramodule, but depends on other type 1 PDZ domain-containing proteins such as SAP97 and Veli, which associate with CASK through its L27 domains. Our data underline the relevance of an intact PSG tandem of CASK for human health.