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Targeting TrkB–PSD-95 coupling to mitigate neurological disorders

Neural Regeneration Research 2025年第3期20卷 715-724页

作者： Xin Yang Yu-Wen Alvin Huang John Marshall Department of Molecular biology Cell Biology and BiochemistryBrown UniversityProvidenceRIUSA Department of Neurology Warren Alpert Medical School of Brown UniversityProvidenceRIUSA Center for Translational Neuroscience Robert J.and Nancy D.Carney Institute for Brain Science and Brown Institute for Translational ScienceBrown UniversityProvidenceRIUSA

Tropomyosin receptor kinase B(TrkB)signaling plays a pivotal role in dendritic growth and dendritic spine formation to promote learning and *** activity-dependent release of brain-derived neurotrophic factor at synapses binds to pre-or postsynaptic TrkB resulting in the strengthening of synapses,reflected by long-term ***,the association of postsynaptic density protein-95 with TrkB enhances phospholipase Cγ-Ca^(2+)/calmodulin-dependent protein kinaseⅡand phosphatidylinositol 3-kinase-mechanistic target of rapamycin signaling required for long-term *** this review,we discuss TrkB-postsynaptic density protein-95 coupling as a promising strategy to magnify brain-derived neurotrophic factor signaling towards the development of novel therapeutics for specific neurological disorders.A reduction of TrkB signaling has been observed in neurodegenerative disorders,such as Alzheimer's disease and Huntington's disease,and enhancement of postsynaptic density protein-95 association with TrkB signaling could mitigate the observed deficiency of neuronal connectivity in schizophrenia and *** with brain-derived neurotrophic factor is problematic,due to poor pharmacokinetics,low brain penetration,and side effects resulting from activation of the p75 neurotrophin receptor or the truncated TrkB.T1 *** TrkB agonists and antibodies that activate TrkB are being intensively investigated,they cannot distinguish the multiple human TrkB splicing isoforms or cell type-specific *** TrkB–postsynaptic density protein-95 coupling provides an alternative approach to specifically boost TrkB signaling at localized synaptic sites versus global stimulation that risks many adverse side effects.

关键词： Angelman syndrome autism brain-derived neurotrophic factor depression neurodegenerative disorder neurodevelopmental disorder postsynaptic density protein-95 synaptic plasticity TrkB

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Crosstalk among canonical Wnt and Hippo pathway members in skeletal muscle and at the neuromuscular junction

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Neural Regeneration Research 2025年第9期20卷 2464-2479页

作者： Said Hashemolhosseini Lea Gessler institute of biochemistry Medical FacultyFriedrich-Alexander-University of Erlangen-NürnbergErlangenGermany

Skeletal muscles are essential for locomotion,posture,and metabolic *** understand physiological processes,exercise adaptation,and muscle-related disorders,it is critical to understand the molecular pathways that underlie skeletal muscle *** process of muscle contra ction,orchestrated by a complex interplay of molecular events,is at the core of skeletal muscle *** contraction is initiated by an action potential and neuromuscular transmission requiring a neuromuscular *** muscle fibers,calcium ions play a critical role in mediating the interaction between actin and myosin filaments that generate *** of calcium release from the sarcoplasmic reticulum plays a key role in excitation-contraction *** development and growth of skeletal muscle are regulated by a network of molecular pathways collectively known as *** regulators coordinate the diffe rentiation of myoblasts into mature muscle *** pathways regulate muscle protein synthesis and hypertrophy in response to mechanical stimuli and nutrient *** ral muscle-related diseases,including congenital myasthenic disorders,sarcopenia,muscular dystrophies,and metabolic myopathies,are underpinned by dys regulated molecular pathways in skeletal *** interventions aimed at preserving muscle mass and function,enhancing regeneration,and improving metabolic health hold promise by targeting specific molecular *** molecular signaling pathways in skeletal muscle include the canonical Wnt signaling pathway,a critical regulator of myogenesis,muscle regeneration,and metabolic function,and the Hippo signaling *** recent years,more details have been uncovered about the role of these two pathways during myogenesis and in developing and adult skeletal muscle fibers,and at the neuromuscular *** fact,research in the last few years now suggests that these two signaling pathways are interconnected and

关键词： canonical Wnt"Wingless-related integration site"pathway beta-catenin(CTNNB1) Hippo pathway myogenesis myotube neuromuscular junction satellite cell skeletal muscle fiber transcriptional co-activator with PDZ-binding motif(TAZ) T-cell-specific transcription factor/lymphoid enhancer-binding factor(TCF/LEF) TEA domain family member(TEAD) transducin-like enhancer of split(TLE) yes-associated protein 1(YAP1)

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Functions of nuclear factor Y in nervous system development,function and health

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Neural Regeneration Research 2025年第10期20卷 2887-2894页

作者： Pedro Moreira Roger Pocock Development and Stem Cells Program Monash Biomedicine Discovery Institute and Department of Anatomy and Developmental BiologyMonash UniversityMelbourneVICAustralia

Nuclear factor Y is a ubiquitous heterotrimeric transcription factor complex conserved across eukaryotes that binds to CCAAT boxes,one of the most common motifs found in gene promoters and *** the last 30 years,research has revealed that the nuclear factor Y complex controls many aspects of brain development,including differentiation,axon guidance,homeostasis,disease,and most recently ***,a complete understanding of transcriptional regulatory networks,including how the nuclear factor Y complex binds to specific CCAAT boxes to perform its function remains *** this review,we explore the nuclear factor Y complex’s role and mode of action during brain development,as well as how genomic technologies may expand understanding of this key regulator of gene expression.

关键词： axon guidance CCAAT boxes neuronal degeneration neuronal differentiation neuronal regeneration nuclear factor Y complex transcription factor transcriptional regulation

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Microglia:a promising therapeutic target in spinal cord injury

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Neural Regeneration Research 2025年第2期20卷 454-463页

作者： Xiaowei Zha Guoli Zheng Thomas Skutella Karl Kiening Andreas Unterberg Alexander Younsi Department of Neurosurgery Heidelberg University HospitalHeidelbergGermany Department of Neuroanatomy Institute for Anatomy and Cell BiologyHeidelberg UniversityHeidelbergGermany

Microglia are present throughout the central nervous system and are vital in neural repair,nutrition,phagocytosis,immunological regulation,and maintaining neuronal *** a healthy spinal cord,microglia are accountable for immune surveillance,however,when a spinal cord injury occurs,the microenvironment drastically changes,leading to glial scars and failed axonal *** this context,microglia vary their gene and protein expression during activation,and proliferation in reaction to the injury,influencing injury responses both favorably and unfavorably.A dynamic and multifaceted injury response is mediated by microglia,which interact directly with neurons,astrocytes,oligodendrocytes,and neural stem/progenitor *** a clear understanding of their essential nature and origin,the mechanisms of action and new functions of microglia in spinal cord injury require extensive *** review summarizes current studies on microglial genesis,physiological function,and pathological state,highlights their crucial roles in spinal cord injury,and proposes microglia as a therapeutic target.

关键词： astrocytes cytokines functional recovery immune regulation M1/M2 activation macrophages microglia neuroinflammation spinal cord injury therapy

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Oligodendroglial heterogeneity in health,disease,and recovery:deeper insights into myelin dynamics

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Neural Regeneration Research 2025年第11期20卷 3179-3192页

作者： Pieter-Jan Serneels Julie D.De Schutter Lies De Groef Lieve Moons Steven Bergmans KU Leuven Leuven Brain InstituteDepartment of BiologyAnimal Physiology and Neurobiology DivisionNeural Circuit Development&Regeneration Research GroupLeuvenBelgium KU Leuven Leuven Brain InstituteDepartment of BiologyAnimal Physiology and Neurobiology DivisionCellular Communication&Neurodegeneration Research GroupLeuvenBelgium

Decades of research asserted that the oligodendroglial lineage comprises two cell types:oligodendrocyte precursor cells and ***,recent studies employing single-cell RNA sequencing techniques have uncovered novel cell states,prompting a revision of the existing *** forward,the oligodendroglial lineage should be delineated into five distinct cell states:oligodendrocyte precursor cells,committed oligodendrocyte precursor cells,newly formed oligodendrocytes,myelin-forming oligodendrocytes,and mature *** new classification system enables a deeper understanding of the oligodendroglia in both physiological and pathological *** this uniform terminology will facilitate comparison and integration of data across ***,including the consolidation of findings from various demyelinating models,is essential to better understand the pathogenesis of demyelinating ***,comparing injury models across species with varying regenerative capacities can provide insights that may lead to new therapeutic strategies to overcome remyelination ***,by standardizing terminology and synthesizing data from diverse studies across different animal models,we can enhance our understanding of myelin pathology in central nervous system disorders such as multiple sclerosis,Alzheimer's disease,and amyotrophic lateral sclerosis,all of which involve oligodendroglial and myelin dysfunction.

关键词： animal models demyelination fish mammals multiple sclerosis myelin neurodegeneration oligodendrocytes oligodendroglial lineage remyelination

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Emerging insights into the function of very long chain fatty acids at cerebellar synapses

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Neural Regeneration Research 2025年第6期20卷 1709-1710页

作者： Martin-Paul Agbaga Mohiuddin Ahmad Department of Cell biology and Ophthalmology University of Oklahoma Health Sciences Centerand Dean McGee Eye InstituteOklahoma CityOKUSA

Very long chain-saturated and-polyunsaturated fatty acids(VLC-SFA and VLC-PUFA, respectively) are a functionally important class of fatty acids containing 28 carbons or more in their acyl chain. They are synthesized by the elongation of very long fatty acids-4(ELOVL4) enzyme, expressed mainly in the brain, retina, skin, testes, and meibomian gland, where these fatty acids are found(Agbaga et al., 2008). Further, these organs exhibit tissuespecific VLC-PUFA and VLC-SFA biosynthesis and incorporation into complex lipids for specific functions. In the brain, skin, and Meibomian glands, the ELOVL4 mainly makes VLC-SFA, which are incorporated into complex sphingolipids. In the retina, the ELOVL4 makes VLC-PUFA that are incorporated into phosphatidylcholine, that are critical for visual function, while in testes and sperm, the VLC-PUFA are incorporated into sphingolipids that are critical for fertility(Yeboah et al., 2021).

关键词： functions function insight

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Small extrachromosomal circular DNA in amyotrophic lateral sclerosis matter

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Neural Regeneration Research 2025年第5期20卷 1411-1413页

作者： Marcos J.Arauzo-Bravo Daniela Gerovska Matthias Schwab Alexandra Kretz Computational biology and Systems Biomedicine Biodonostia Health Research InstituteSan SebastianSpain Basque Foundation for Science IKERBASQUEBilbaoSpainMax Planck Institute for Molecular BiomedicineComputational Biology and Bioinformatics GroupMünsterNorth Rhine-WestphaliaGermany Department of Cell biology and Histology Faculty of Medicine and NursingUniversity of Basque Country(UPV/EHU)LeioaSpain Department of Neurology Jena University HospitalJenaThuringiaGermany

Comprehensive studies identify motor neuron spectrum disorders including amyotrophic lateral sclerosis(ALS)as globally rising fatal disorders with the highest prevalence in aging populations,influenced by ethnicity and ancestry(GBD 2016 Motor Neuron Disease Colla borators,2018).While~10% of diagnoses involve a family history(fALS),most cases are considered sporadic(sALS).However,population-based studies suggest that even cases without a common index mutation impart heritability(Ryan et al.,2019),indicating a crucial role of rare and as yet unknown genetic denominators.

关键词： amyotrophic sclerosis

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Neuroinflammation revisited through the microglial lens

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Neural Regeneration Research 2025年第7期20卷 1989-1990页

作者： Renato Socodato João B.Relvas institute of Research and Innovation in Health(i3S)and institute for Molecular and Cell biology(IBMC) University of PortoPortoPortugal Department of Biomedicine Faculty of Medicine of the University of Porto(FMUP)PortoPortugal

Neuroimmunology is emerging as a pivotal field,shedding light on the intricate dialogues between the central nervous system(CNS)and the immune *** exploration is particularly significant in understanding microglia,the CNS’s innate immune cells,beyond the conventional conflation of“neuroinflammation”and“microglial activation.”This conflation has clouded the true complexity of these processes,potentially stalling scientific progress and the development of new *** challenge the long-standing perspectives that have oversimplified these interactions,advocating for a deeper exploration of the dynamic relationship between neuroinflammation and microglial *** dissecting specific molecular pathways,we aim to illuminate their elaborate roles in neuroinflammatory responses,especially in the context of Alzheimer’s disease(AD).Here,neuroinflammation is not merely a passive observer or a direct antagonist but a complex agent in the disease’s *** article calls for a significant paradigm shift towards an integrative,multi-omics approach to *** such a comprehensive framework is crucial for advancing our understanding of neuroinflammatory conditions and paving the way for targeted therapeutic strategies for brain diseases.

关键词： inflammation simplified activation

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Genes and proteins expressed at different life cycle stages in the model protist Euplotes vannus revealed by both transcriptomic and proteomic approaches

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Science China Life Sciences 2025年第1期68卷 232-248页

作者： Yaohan Jiang Xiao Chen Chundi Wang Liping Lyu Saleh A.Al-Farraj Naomi A.Stover Feng Gao Key Laboratory of Evolution & Marine Biodiversity (Ministry of Education) and institute of Evolution & Marine Biodiversity Ocean University of China Marine College Shandong University Zoology Department College of ScienceKing Saud University Department of biology Bradley University Laboratory for Marine biology and Biotechnology Qingdao Marine Science and Technology Center

Sexual reproduction first appeared in unicellular protists and has continued to be an essential biological process in almost all *** protists, which contain both germline and somatic genomes within a single cell, have evolved a special form of sexual reproduction called conjugation that involves mitosis, meiosis, fertilization, nuclear differentiation, genome rearrangement, and the development of unique cellular structures. The molecular basis and mechanisms of conjugation vary dramatically among ciliates, and many details of the process and its regulation are still largely unknown. In order to better comprehend these processes and mechanisms from an evolutionary perspective, this study provides the first comprehensive overview of the transcriptome and proteome profiles during the entire life cycle of the newly-established marine model ciliate Euplotes vannus. Transcriptome analyses from 14 life cycle stages(three vegetative stages and 11 sexual stages) revealed over 26,000 genes that are specifically expressed at different stages, many of which are related to DNA replication,transcription, translation, mitosis, meiosis, nuclear differentiation, and/or genome rearrangement. Quantitative proteomic analyses identified 338 proteins with homologs associated with conjugation and/or somatic nuclear development in other ciliates, including dicer-like proteins, Hsp90 proteins, RNA polymerase Ⅱ and transcription elongation factors, ribosomal-associated proteins, and ubiquitin-related proteins. Four of these homologs belong to the PIWI family, each with different expression patterns identified and confirmed by RT-qPCR,which may function in small RNA-mediated genome rearrangement. Proteins involved in the nonhomologous end-joining pathway are induced early during meiosis and accumulate in the developing new somatic nucleus, where more than 80% of the germline sequences are eliminated from the somatic genome. A number of new candidate genes and proteins likely t

关键词： sexual reproduction transcriptomic proteomic genome rearrangement PIWI NHEJ

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Remaking a connection:molecular players involved in post-injury synapse formation

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Neural Regeneration Research 2025年第6期20卷 1719-1720页

作者： Diogo Tomé Ramiro D.Almeida iBiMED-institute of Biomedicine Department of Medical SciencesUniversity of AveiroAveiroPortugal CNC-Center for Neuroscience and Cell biology University of CoimbraCoimbraPortugal

Functional recovery from central nervous system(CNS)trauma depends not only on axon regeneration or compensatory sprouting of uninjured fibers but also on the ability of newly grown axons to establish functional synapses with appropriate *** several studies have successfully promoted long-distance axonal regeneration in distinct CNS injury models,none of them have resulted in a viable therapeutic approach for patient recovery.A possible reason may be the lack of new synaptogenesis for reestablishing the circuitry lost after ***,we discuss how our understanding of the mechanisms that instruct synapse formation in the injured nervous system may contribute to the design of new strategies to promote functional restoration in traumatic CNS disorders.

关键词： viable injury instru

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