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Effects of P301L-TAU on post-translational modifications of microtubules in human iPSC-derived cortical neurons and TAU transgenic mice

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Neural Regeneration Research 2025年第8期20卷 2348-2360页

作者： Mohamed Aghyad Al Kabbani Christoph Köhler Hans Zempel Institute of Human genetics Faculty of Medicine and University Hospital CologneUniversity of CologneCologneGermany Center for molecular Medicine Cologne(CMMC) University of CologneCologneGermany Center Anatomy Department ⅡMedical FacultyUniversity of CologneCologneGermany

TAU is a microtubule-associated protein that promotes microtubule assembly and stability in the *** is missorted and aggregated in an array of diseases known as *** are essential for neuronal function and regulated via a complex set of post-translational modifications,changes of which affect microtubule stability and dynamics,microtubule interaction with other proteins and cellular structures,and mediate recruitment of microtubule-severing *** impairment of microtubule dynamics causes neuronal dysfunction,we hypothesize cognitive impairment in human disease to be impacted by impairment of microtubule *** therefore aimed to study the effects of a disease-causing mutation of TAU(P301L)on the levels and localization of microtubule post-translational modifications indicative of microtubule stability and dynamics,to assess whether P301L-TAU causes stability-changing modifications to *** investigate TAU localization,phosphorylation,and effects on tubulin post-translational modifications,we expressed wild-type or P301L-TAU in human MAPT-KO induced pluripotent stem cell-derived neurons(i Neurons)and studied TAU in neurons in the hippocampus of mice transgenic for human P301L-TAU(p R5 mice).Human neurons expressing the longest TAU isoform(2N4R)with the P301L mutation showed increased TAU phosphorylation at the AT8,but not the p-Ser-262 epitope,and increased polyglutamylation and acetylation of microtubules compared with endogenous TAU-expressing neurons.P301L-TAU showed pronounced somatodendritic presence,but also successful axonal enrichment and a similar axodendritic distribution comparable to exogenously expressed 2N4R-wildtype-TAU.P301L-TAU-expressing hippocampal neurons in transgenic mice showed prominent missorting and tauopathy-typical AT8-phosphorylation of TAU and increased polyglutamylation,but reduced acetylation,of microtubules compared with non-transgenic *** sum,P301L-TAU results in changes in micr

关键词： human induced pluripotent stem cell microtubules P301L pR5 mice TAU tauopathy tubulin code

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Therapeutic targeting of cellular prion protein: toward the development of dual mechanism anti-prion compounds

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Neural Regeneration Research 2025年第4期20卷 1009-1014页

作者： Antonio Masone Chiara Zucchelli Enrico Caruso Giovanna Musco Roberto Chiesa Laboratory of Prion Neurobiology Department of NeuroscienceIstituto di Ricerche Farmacologiche Mario Negri IRCCSMilanItaly Biomolecular NMR Unit Division of Genetics and Cell BiologyIRCCS Ospedale San RaffaeleMilanItaly department of Biotechnology and Life Sciences University of InsubriaVareseItaly

PrPSc,a misfolded,aggregation-prone isoform of the cellular prion protein(PrPC),is the infectious prion agent responsible for fatal neurodegenerative diseases of humans and other *** adopt different pathogenic conformations(prion strains),which can be resistant to potential drugs,or acquire drug resistance,posing challenges for the development of effective *** PrPCis the obligate precursor of any prion strain and serves as the mediator of prion neurotoxicity,it represents an attractive therapeutic target fo r prion *** this minireview,we briefly outline the approaches to target PrPCand discuss our recent identification of Zn(Ⅱ)-Bn PyP,a PrPC-targeting porphyrin with an unprecedented bimodal mechanism of *** argue that in-depth understanding of the molecular mechanism by which Zn(Ⅱ)-Bn PyP targets PrPCmay lead toward the development of a new class of dual mechanism anti-prion compounds.

关键词： anti-prion drug anti-PrPC antibody antisense oligonucleotide neurodegeneration pharmacological chaperone porphyrin prion disease PrPC degrader PrPC shedding zinc finger repressor

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Genetic and epigenetic alterations associated with gestational diabetes mellitus and adverse neonatal outcomes

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World Journal of Clinical Pediatrics 2025年第1期14卷 6-20页

作者： Amreen Shamsad Tanu Gautam Renu Singh Monisha Banerjee molecular and Human genetics Laboratory Department of ZoologyUniversity of LucknowLucknow 226007Uttar PradeshIndia department of Obstetrics and Gynecology King George’s Medical UniversityLucknow 226003Uttar PradeshIndia

Gestational diabetes mellitus(GDM)is a metabolic disorder,recognised during 24-28 weeks of *** is linked with adverse newborn outcomes such as macrosomia,premature delivery,metabolic disorder,cardiovascular,and neurological *** investigations have focused on the correlation of genetic factors such asβ-cell function and insulin secretary genes(transcription factor 7 like 2,potassium voltage-gated channel subfamily q member 1,adipo-nectin etc.)on maternal metabolism during gestation leading to *** alterations like DNA methylation,histone modification,and miRNA expression can influence gene expression and play a dominant role in feto-maternal meta-bolic *** between genes and environment,resulting in differ-ential gene expression patterns may lead to *** suggested that GDM women are more susceptible to insulin resistance,which alters intrauterine surroundings,resulting hyperglycemia and *** modi-fications in genes affecting neuroendocrine activities,and metabolism,increase the risk of obesity and type 2 diabetes in *** is currently no treatment or effective preventive method for GDM,since the molecular processes of insulin resistance are not well *** present review was undertaken to un-derstand the pathophysiology of GDM and its effects on adverse neonatal *** addition,the study of genetic and epigenetic alterations will provide lead to researchers in the search for predictive molecular biomarkers.

关键词： Gene expression Gestational diabetes mellitus Feto-maternal outcome Epigenetic alteration molecular biomarkers

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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

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Novel Insights from Live-imaging in Shoot Meristem Development

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Journal of Integrative Plant biology 2010年第4期52卷 393-399页

作者： Paja Sijacic department of Cell biology and molecular genetics University of MarylandCollege Park

Microscopic imaging of fluorescent reporters for key meristem regulators in live tissues is emerging as a powerful technique, enabling researchers to observe dynamic spatial and temporal distribution of hormonal and developmental regulators in living cells. Aided by time-lapse microphotography, new types of imaging acquisition and analysis software, and computational modeling, we are gaining significant insights into shoot apical meristem （SAM） behavior and function. This review is focused on summarizing recent advances in the understanding of SAM organization, development, and behavior derived from live-imaging techniques. This includes the revelation of mechanical forces in microtubule-controlled anisotropic growth, the role of the CLV-WUS network in the specification of peripheral zone and central zone cells, the multiple feedback loops involving cytokinin in controlling WUS expression, auxin dynamics in determining the position of new primordia, and, finally, sequence of regulatory events leading to de novo assembly of shoots from callus in culture. Future studies toward formulating ＂digital SAM＂ that incorporates multi-dimensional data ranging from images of SAM morphogenesis to a genome-scale expression map of SAM will greatly enhance our ability to understand, predict, and manipulate SAM, containing the stem cells that give rise to all above ground parts of a plant.

关键词： Novel Insights from Live-imaging in Shoot Meristem Development

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No Home without Hormones: How Plant Hormones Control Legume Nodule Organogenesis

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Plant Communications 2020年第5期1卷 21-40页

作者： Jieshun Lin Manuel Frank Dugald Reid department of molecular biology and genetics Aarhus UniversityAarhusDenmark

The establishment of symbiotic nitrogen fixation requires the coordination of both nodule development and infection *** the evolution of a variety of anatomical structures,nodule organs serve a common purpose in establishing a localized area that facilitates efficient nitrogen *** in all plant developmental processes,the establishment of a new nodule organ is regulated by plant *** nodule initiation,regulation of plant hormone signaling is one of the major targets of symbiotic *** review the role of major developmental hormones in the initiation of the nodule organ and argue that the manipulation of plant hormones is a key requirement for engineering nitrogen fixation in non-legumes as the basis for improved food security and sustainability.

关键词： nitrogen fixation symbiosis hormones nodule legume

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Endless Hide-and-Seek： Dynamic Co-evolution in Plant-Bacterium Warfare

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Journal of Integrative Plant biology 2007年第1期49卷 105-111页

作者： Libo Shan Ping He Jen Sheen department of molecular biology Massachusetts General Hospital and Department of Genetics Boston Massachusetts 02114 USA

Plants possess innate Immune systems to prevent most potential Infections. The ancient and conserved innate immune responses are triggered by microbe-associated molecular patterns （MAMPs） and play important roles in broad-spectrum defenses. However, successful bacterial pathogens evolved type Ⅲ virulence effectors to suppress MAMP-medlated immunity. To survive, plants further developed highly specific resistance （R） genes to trigger gene-for-gene-mediated immunity and turn the virulent pathogens into avirulent ones. We summarize here the very recent advances in this dynamic coevolution of plantbacterium interaction.

关键词： MAMP type Ⅲ effector gene-for-gene resistance

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Selfish genetic elements and the gene＇s-eye view of evolution

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Current Zoology 2016年第6期62卷 659-665页

作者： J. Arvid AGREN department of molecular biology and genetics Cornell University Ithaca NY 14853-2703 USA

During the last few decades, we have seen an explosion in the influx of details about the biology of selfish genetic elements. Ever since the early days of the field, the gene＇s-eye view of Richard Dawkins, George Williams, and others, has been instrumental to make sense of new empirical observations and to the generation of new hypotheses. However, the close association between selfish genetic elements and the gene＇s-eye view has not been without critics and several other conceptual frameworks have been suggested. In particular, proponents of multilevel selection models have used selfish genetic elements to criticize the gene＇s-eye view. Ln this paper, t first trace the intertwined histories of the study of selfish genetic elements and the gene＇s-eye view and then discuss how their association holds up when compared with other proposed frameworks. Next, using examples from transposable elements and the major transitions, I argue that different models highlight separate aspects of the evolution of selfish genetic elements and that the productive way forward is to maintain a plurality of perspectives. Finally, I discuss how the empirical study of selfish genetic elements has implications for other conceptual issues associated with the gene＇seye view, such as agential thinking, adaptationism, and the role of fitness maximizing models in evolution.

关键词： hierarchy intragenomic conflict levels of selection major transitions multilevel selection Richard Dawkins.

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Genome-wide identification and in silico gene expression analysis of the related to ABI3/VP1(RAV)transcription factor family in barley(Hordeum vulgare L.)

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BIOCELL 2021年第6期45卷 1673-1685页

作者： CÜNEYT UÇARLI department of molecular biology and genetics Istanbul UniversityIstanbul34134Turkey

RAV(Related to ABI3/VP1)transcription factors are unique members of the AP2-ERF superfamily with AP2 and B3 domains and play important roles in the regulation of seed germination,plant growth,and stress *** the study,7 RAV genes,named HvRAVs,were identified in barley based on the available genome *** five of the seven HvRAVs were located on chromosome 3,HvRAV5 and HvRAV7 were located on chromosome 1 and 4,*** of the predicted HvRAVs were intron-less,except HvRAV2,which had one *** proteins have shown basic,instable,and hydrophilic *** AP2 domain specific RAYD and WLG motifs were detected in all HvRAV ***,B3 repression domain,R/KLFGV,is also found in the C-terminal of *** were found to have stress-related cis-acting elements,including MYB,MYC,and ***2 was predicted to have no GARE motifs,TATCCCA or TAACAA(G/A),and *** drought conditions,the expression level of HvRAVs did not significantly change in a drought-sensitive barley genotype,whereas HvRAV5 and HvRAV7 were dramatically down-regulated in a drought-tolerant *** of HvRAV5 was also inhibited by ***7 was strongly induced by plant pathogen *** HvRAV6 was induced by exogenous gibberellin application and during the germination ***,HvRAV6 transcript was detected higher than other HvRAVs in all stress and control conditions as well as during *** silico analyses have shown that HvRAVs play a role in response to different abiotic and biotic stresses as well as in plant ***,the extensive biological roles of HvRAV genes in plant development and in response to abiotic and biotic stresses need further investigation.

关键词： Barley RAV AP2 domain B3 domain AP2/ERF family Cis-acting elements

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Stem cells:a promising candidate to treat neurological disorders

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Neural Regeneration Research 2018年第7期13卷 1294-1304页

作者： Chang-Geng Song Yi-Zhe Zhang Hai-Ning Wu Xiu-Li Cao Chen-Jun Guo Yong-Qiang Li Min-Hua Zheng Hua Han department of Medical genetics and Developmental biology Fourth Military Medical University department of Biochemistry and molecular biology Fourth Military Medical University

Neurologic impairments are usually irreversible as a result of limited regeneration in the central nervous ***,based on the regenerative capacity of stem cells,transplantation therapies of various stem cells have been tested in basic research and preclinical trials,and some have shown great *** manuscript overviews the cellular and molecular characteristics of embryonic stem cells,induced pluripotent stem cells,neural stem cells,retinal stem/progenitor cells,mesenchymal stem/stromal cells,and their derivatives in vivo and in vitro as sources for regenerative *** cells have all been considered as candidates to treat several major neurological disorders and diseases,owing to their self-renewal capacity,multi-directional differentiation,neurotrophic properties,and immune modulation *** also review representative basic research and recent clinical trials using stem cells for neurodegenerative diseases,including Parkinson＇s disease,Alzheimer＇s disease,and age-related macular degeneration,as well as traumatic brain injury and *** spite of a few unsuccessful cases,risks of tumorigenicity,and ethical concerns,most results of animal experiments and clinical trials demonstrate efficacious therapeutic effects of stem cells in the treatment of nervous system *** summary,these emerging findings in regenerative medicine are likely to contribute to breakthroughs in the treatment of neurological ***,stem cells are a promising candidate for the treatment of nervous system diseases.

关键词： nerve regeneration stem cells transplantation stem cell therapy nervous system neurodegenerative disease neurological disorders animal experiment clinical trial regenerative medicine neural regeneration

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