Journal of Neurochemistry最新文献

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.

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.

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.

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.” Journal of Neurochemistry 170: e70338. https://onlinelibrary.wiley.com/doi/10.1111/jnc.70338.

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In “Primer name” of TABLE 1, the text “Drd1a F1 (#)” was incorrect.

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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.” eNeuro. https://doi.org/10.1523/ENEURO.0088-25.2025.” was incorrect.

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.” eNeuro 13(1) ENEURO.0088-25.2025.”

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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.

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.