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Targeting TrkB–PSD-95 coupling to mitigate neurological disorders

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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

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

New aspects of a small GTPase RAB35 in brain development and function

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Neural Regeneration Research 2025年第7期20卷 1971-1980页

作者： Ikuko Maejima Ken Sato Laboratory of molecular Traffic Institute for Molecular and Cellular RegulationGunma UniversityMaebashiJapan

In eukaryotic cells,organelles in the secretory,lysosomal,and endocytic pathways actively exchange biological materials with each other through intracellular membrane trafficking,which is the process of transporting the cargo of proteins,lipids,and other molecules to appropriate compartments via transport vesicles or *** processes are strictly regulated by various small GTPases such as the RAS-like in rat brain(RAB)protein family,which is the largest subfamily of the RAS *** of membrane trafficking affects tissue homeostasis and leads to a wide range of diseases,including neurological disorders and neurodegenerative ***,it is important to understand the physiological and pathological roles of RAB proteins in brain ***35,a member of the RAB family,is an evolutionarily conserved protein in metazoans.A wide range of studies using cultured mammalian cells and model organisms have revealed that RAB35 mediates various processes such as cytokinesis,endocytic recycling,actin bundling,and cell ***35 is also involved in neurite outgrowth and turnover of synaptic *** generated brain-specific Rab35 knockout mice to study the physiological roles of RAB35 in brain development and *** mice exhibited defects in anxiety-related behaviors and spatial ***,RAB35 is required for the precise positioning of pyramidal neurons during hippocampal development,and thereby for normal hippocampal *** contrast,layer formation in the cerebral cortex occurred superficially,even in the absence of RAB35,suggesting a predominant role for RAB35 in hippocampal development rather than in cerebral cortex *** studies have suggested an association between RAB35 and neurodegenerative diseases,including Parkinson's disease and Alzheimer's *** this review,we provide an overview of the current understanding of subcellular functions of *** also provide insights into the phys

关键词： endocytosis endosomes hippocampal development neurodegenerative diseases RAB35

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

Sequence-activated chemiluminescence probes: programmable illumination for high-contrast in vivo sensing and imaging

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Science China Chemistry 2025年第1期68卷 26-34页

作者： Yutao Zhang Juan Li Wei-Hong Zhu Zhiqian Guo Shanghai Key Laboratory of Functional Materials Chemistry Joint International Research Laboratory of Precision Chemistry and Molecular Engineering Institute of Fine Chemicals School of Chemistry and Molecular Engineering East China University of Science and Technology State Key Laboratory of Bioreactor Engineering Shanghai Frontier Science Research Base of Optogenetic Techniques for Cell MetabolismEast China University of Science & Technology

Sequence-activated chemiluminescence(CL) technique offers a unique approach to detecting specific biomolecules or cellular events with high sensitivity and spatial resolution. The fundamental principle behind sequence-activated CL probes involves tailoring highly-controllable CL signals in response to specific sequences or events of interest, thus enabling high-contrast signals under complex physiological conditions. This sequential activation could be triggered by enzymes, reactive oxygen species(ROS), biothiols or changes in the microenvironment. These unique sequence-activated CL probes bestow several advantages, including minimal background, deep-tissue penetration, and the ability of non-invasive or minimally invasive detection. The sequence-activated CL techniques represent a significant advancement in molecular imaging and diagnostics. In this mini-review, we focus on the latest developments in sequential CL probes, addressing the technical challenges and discussing the future trajectory by harnessing CL signaling and molecular recognition.

关键词： chemiluminescnece sequence-activation in-vivo bioimaging cyclic peroxide

Tangled but ordered human mitochondrial tRNA maturation

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Science China Life Sciences 2025年

作者： Shi-Ying Yao Xiao-Long Zhou Key Laboratory of RNA Innovation Science and Engineering CAS Center for Excellence in Molecular Cell Science Shanghai Institute of Biochemistry and Cell Biology Chinese Academy of Sciences University of Chinese Academy of Sciences Key Laboratory of Systems Health Science of Zhejiang Province School of Life Science Hangzhou Institute for Advanced Study University of Chinese Academy of Sciences

Mitochondria are cellular organelles that originate from an endosymbiotic bacterial ancestor and are primarily responsible for ATP generation via oxidative phosphorylation (OXPHOS). OXPHOS is conducted by five mitochondrial respiratory complexes in the inner mitochondrial membrane. Human mitochondria possess a distinct genome, a small, circular, doublestranded DNA (mtDNA) of 16,569 base pairs.

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Die in pieces:How Drosophila sheds light on neurite degeneration and clearance

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Journal of Genetics and Genomics 2019年第4期46卷 187-199页

作者： Maria L.Sapar Chun Han weill institute for cell and molecular biology Department of Molecular Biology and GeneticsCornell University

Dendrites and axons are delicate neuronal membrane extensions that undergo degeneration after physical injuries. In neurodegenerative diseases, they often degenerate prior to neuronal death. Understanding the mechanisms of neurite degeneration has been an intense focus of neurobiology research in the last two decades. As a result, many discoveries have been made in the molecular pathways that lead to neurite degeneration and the cell-cell interactions responsible for the subsequent clearance of neuronal debris. Drosophila melanogaster has served as a prime in vivo model system for identifying and characterizing the key molecular players in neurite degeneration, thanks to its genetic tractability and easy access to its nervous system. The knowledge learned in the fly provided targets and fuel for studies in other model systems that have further enhanced our understanding of neurodegeneration. In this review, we will introduce the experimental systems developed in Drosophila to investigate injuryinduced neurite degeneration, and then discuss the biological pathways that drive degeneration. We will also cover what is known about the mechanisms of how phagocytes recognize and clear degenerating neurites, and how recent findings in this area enhance our understanding of neurodegenerative disease pathology.

关键词： Drosophila Neurite degeneration Axon Dendrite Wallerian degeneration Phagocyte Phagocytosis PS exposure Injury assay

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

The Sac domain-containing phosphoinositide phosphatases： structure, function, and disease

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Frontiers in biology 2013年第4期8卷 395-407页

作者： FoSheng HSU Yuxin MAO weill institute for cell and molecular biology and Department of molecular biology and Genetics Cornell University Ithaca NY 14853USA

Phosphoinositides （Pls） have long been known to have an essential role in cell physiology. Their intracellular localization and concentration must be tightly regulated for their proper function. This spatial and temporal regulation is achieved by a large number of PI kinases and phosphatases that are present throughout eukaryotic species. One family of these enzymes contains a conserved PI phosphatase domain termed Sac. Although the Sac domain is homologous among different Sac domain-containing proteins, all appear to exhibit varied substrate specificity and subcellular localization. Dysfunctions in several members of this family are implicated in a range of human diseases such as cardiac hypertrophy, bipolar disorder, Down＇s syndrome, Charcot-Marie-Tooth disease （CMT） and Amyotrophic Lateral Sclerosis （ALS）. In plant, several Sac domain-containing proteins have been implicated in the stress response, chloroplast function and polarized secretion. In this review, we focus on recent findings in the family of Sac domain-containing PI phosphatases in yeast, mammal and plant, including the structural analysis into the mechanism of enzymatic activity, cellular functions, and their roles in disease pathophysiology.

关键词： lipid metabolism membrane trafficking