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Expression of human FUS/TLS in yeast leads to protein aggregation and cytotoxicity,recapitulating key features of FUS proteinopathy

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protein & Cell 2011年第2期2卷 141-149页

作者： Kazuo Fushimi Charles Long Neha Jayaram Xiaoping Chen Liming Li Jane Y.Wu Department of Neurology Center for Genetic MedicineLurie Comprehensive Cancer CenterNorthwestern University Feinberg School of Medicine303 E.SuperiorChicagoIL 60611USA Department of Molecular Pharmacology and Biological Chemistry Northwestern University Feinberg School of Medicine303 E.SuperiorChicagoIL 60611USA

Mutations in the fused in sarcoma/translocated in liposarcoma(FUS/TLS)gene have been associated with amyotrophic lateral sclerosis(ALS).FUS-positive neuropathology is reported in a range of neurodegenerative diseases,including ALS and fronto-temporal lobar degeneration with ubiquitin-positive pathology(FTLDU).To examine protein aggregation and cytotoxicity,we expressed human FUS protein in *** of either wild type or ALS-associated R524S or P525L mutant FUS in yeast cells led to formation of aggregates and cytotoxicity,with the two ALS mutants showing increased ***,yeast cells expressing human FUS protein recapitulate key features of FUSpositive neurodegenerative ***,a significant fraction of FUS expressing yeast cells stained by propidium iodide were without detectable protein aggregates,suggesting that membrane impairment and cellular damage caused by FUS expression may occur before protein aggregates become microscopically detectable and that aggregate formation might protect cells from FUS-mediated *** N-terminus of FUS,containing the QGSY and G rich regions,is sufficient for the formation of aggregates but not *** C-terminal domain,which contains a cluster of mutations,did not show aggregation or *** to TDP-43 when expressed in yeast,FUS protein has the intrinsic property of forming aggregates in the absence of other human *** the other hand,the aggregates formed by FUS are thioflavin T-positive and resistant to 0.5%sarkosyl,unlike TDP-43 when expressed in yeast ***,TDP-43 and FUS display distinct domain requirements in aggregate formation and cytotoxicity.

关键词： FUS/TLS protein aggregation cytotoxicity

Pyropia haitanensis polysaccharide extends lifespan by inhibiting protein aggregation in Caenorhabditis elegans

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Journal of Oceanology and Limnology 2021年第2期39卷 705-713页

作者： Zhongshan ZHANG Xiaomei WANG Yongliang PAN Zhanqi WANG Zhengshun WEN Feng LIU Genxiang MAO Key Laboratory of Vector Biology and Pathogen Control of Zhejiang Province Huzhou UniversityHuzhou Central HospitalHuzhou 313000China Zhejiang Provincial Engineering Technology Research Center of Marine Biomedical Products School of Food Science and PharmaceuticsZhejiang Ocean UniversityZhoushan 316022China CAS Key Laboratory of Marine Ecology and Environmental Sciences Institute of OceanologyChinese Academy of SciencesQingdao 266071China Zhejiang Provincial Key Lab of Geriatrics Department of GeriatricsZhejiang HospitalHangzhou 310013China

Pyropia haitanensis polysaccharide(LP)have been found for having many excellent functions such as *** Caenorhabditis elegans models,we evaluated the anti-aging activity of LP by observing the lifespan,reproduction,pharyngeal pumping,stress response,quantitative fluorescence of polyglutamic acid,and nuclear localization of DAF-16 of *** results reveal that LP could extend the adult lifespan of wild-type and polyQ nematodes,indicating a connection of its anti-aging benefit with the toxicity-suppressing *** number of polyglutamic acid aggregates in high concentration groups decreased by 24.39%(Pprotein aggregation in *** through nuclear DAF-16∷GFP expression.

关键词： Pyropia haitanensis polysaccharide protein aggregation Caenorhabditis elegans

Requirement of Zn2+ for ischemia-induced ubiquitin conjugation and protein aggregation in rat hippocampus

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Requirement of Zn2+ for ischemia-induced ubiquitin conjugati...

Installing hydrogen bonds as a general strategy to control viscosity sensitivity of molecular rotor fluorophores Special Collection:aggregation-Induced Processes and Functions

中国神经科学学会第四次会员代表大会暨第七届全国学术会议

作者： Min CHEN,Zhi-Qi XIONG Institute of Neuroscience,Shanghai Institutes for Biological Sciences,Chinese Acndemy of Sciences,Shanghai 200031, China

The ubiquitin-proteasome system(UPS) is the major degradation pathway for intracellular *** impairment and/or overload of the ubiquitin-proteasome pathway are likely to be major contributors to neurodegeneration. Deposition of ubiquitinated protein aggregates is a common hallmark of neurodegeneration in both acute conditions,such as stroke,and chronic neurodegenerative conditions,such as Parkinson’s disease,but the underlying mechanisms are poorly *** we report that ubiquitin conjugation and protein aggregation increased in the CA1 region of rat hippocampus after transient forebrain *** endogenous Zn with CaEDTA reduced ischemia-induced ubiquitin conjugation,protein ***,exposure to zinc chloride increased ubiquitin conjugation and inhibited the proteasome enzymic activity in cultured hippocampal neurons in a concentration- and time-dependent ***,Zn mediated ischemia-induced ubiquitin conjugation and protein aggregation in the *** predict that alterations in Zn homeostasis will impair protein quality control/degradation pathway and may contribute to the pathogeneses of diverse human neurological diseases.

关键词： forebrain ischemia hippocampus ubiquitin conjugation protein aggregation the proteasome neurodegeneration

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Aggregate

Aggregate 2024年第1期5卷 367-376页

作者： Baoxing Shen Lihua Liu Yubo Huang Jichun Wu Huan Feng Yu Liu He Huang Xin Zhang Department of Chemistry Research Center for Industries of the FutureWestlake UniversityHangzhouChina Westlake Laboratory of Life Sciences and Biomedicine HangzhouChina School of Food Science and Pharmaceutical Engineering Nanjing Normal UniversityNanjingChina CAS Key Laboratory of Separation Science for Analytical Chemistry Dalian Institute of Chemical PhysicsChinese Academy of SciencesDalianChina

Molecular rotor-based fluorophores(RBFs)activate fluorescence upon increase of micro-viscosity,thus bearing a broad application promise in many ***,it remains a challenge to control how fluorescence of RBFs responds to viscosity ***,we demonstrate that the formation and regulation of intramolecular hydrogen bonds in the excited state of RBFs could modulate their rotational barrier,leading to a rational control of how their fluorescence can be activated by *** on this strategy,a series of RBFs were developed based on 4-hydroxybenzylidene-imidazolinone(HBI)that span a wide range of viscosity *** with the AggTag method that we previously reported,the varying viscosity sensitivity and emission spectra of these probes enabled a dualcolor imaging strategy that detects both protein oligomers and aggregates during the multistep aggregation process of proteins in live *** summary,our work indicates that installing intracellular excited state hydrogen bonds to RBFs allows for a rational control of rotational barrier,thus allow for a fine tune of their viscosity *** RBFs,we envision similar strategies can be applied to control the fluorogenic behavior of a large group of fluorophores whose emission is dependent on excited state rotational motion,including aggregation-induced emission fluorophores.

关键词： fluorescent probe intramolecular hydrogen bond protein aggregation rotor-based fluorophores viscosity sensitivity

Solution pH jump during antibody and Fc-fusion protein thaw leads to increased aggregation

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Journal of Pharmaceutical Analysis 2018年第5期8卷 302-306页

作者： Kevin P.Kent Chad E.Schroeder Chandana Sharma Upstream R&D MilliporeSigma

Freeze-thaw cycles impact the amount of aggregation observed in antibodies and Fc-fusion proteins. Various formulation strategies are used to mitigate the amount of aggregation that occurs upon putting a protein solution through a freeze-thaw cycle. Additionally, low pH solutions cause native antibodies to unfold, which are prone to aggregate upon pH neutralization, There is great interest in the mechanism that causes therapeutic proteins to aggregate since aggregate species can cause unwanted immunogenicity in patients, Herein, an increase in aggregation is reported when the pH is adjusted from pH 3 up to a pH ranging from pH 4 to pH 7 during the thaw process of a frozen antibody solution, Raising the pH during the thaw process caused a significant increase in the percent aggregation observed. Two antibodies and one Fc-fusion protein were evaluated during the pH jump thaw process and similar effects were observed. The results provide a new tool to study the kinetics of therapeutic protein ag- gregation upon pH increase,

关键词： Monoclonal antibodies Freeze-thaw protein aggregation protein stability

Nanomaterials for neurodegenerative diseases:Molecular mechanisms guided design and applications

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Nano Research 2022年第4期15卷 3299-3322页

作者： Tianzhong Li Xueyan Hou Yu Qi Xiaohan Duan Pengcheng Yan Haoru Zhu Zhongjian Xie Han Zhang Shenzhen International Institute for Biomedical Research Shenzhen 518110China International Collaborative Laboratory of 2D Materials for Optoelectronics Science and Technology of Ministry of Education Institute of Microscale OptoelectronicsShenzhen UniversityShenzhen 518060China School of Pharmaceutical Sciences Wenzhou Medical UniversityWenzhou 325035China Institute of Pediatrics Shenzhen Children’s HospitalShenzhen 518038China

Successful treatment of neurodegenerative diseases(NDDs),including Alzheimer’s disease(AD),Parkinson’s disease(PD),and Huntington’s disease(HD),remains a significant challenge for neurologists due to the undesirable curative *** from surgeries,most drugs are only used to relieve the patients’symptoms without a permanent cure of the *** development of novel biomaterials targeting NDDs is greatly hindered by the limited understanding of underlying molecular *** the difficulties in NDD drug development and clinical trials,a comprehensive and up-to-date review of disease pathogenesis and related novel therapies are *** the current article,the basic concepts and pathogenic characteristics of NDDs are firstly *** the detailed description of molecular mechanisms underlying three common NDDs,recent advances of drug development based on targeting different pathogenic mechanisms are ***,this review will be beneficial to address the gap between materials and targeted mechanisms while simultaneously provide suggestions for the future design of precise NDD medicine.

关键词： neurodegenerative diseases molecular mechanisms nanomaterials signaling pathways protein aggregation

α-Synuclein oligomers and fibrils:partners in crime in synucleinopathies

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Neural Regeneration Research 2023年第11期18卷 2332-2342页

作者： Alessandra Bigi Roberta Cascella Cristina Cecchi Department of Experimental and Clinical Biomedical Sciences Section of BiochemistryUniversity of FlorenceFlorenceItaly

The misfolding and aggregation of a-synuclein is the general hallmark of a group of devastating neurodegenerative pathologies referred to as synucleinopathies,such as Parkinson’s disease,dementia with Lewy bodies,and multiple system *** such conditions,a range of different misfolded aggregates,including oligomers,protofibrils,and fibrils,are present both in neurons and glial *** expe rimental evidence supports the proposition that solu ble oligomeric assemblies,formed during the early phases of the aggregation process,are the major culprits of neuronal toxicity;at the same time,fibrillar confo rmers appear to be the most efficient at propagating among interconnected neurons,thus contributing to the spreading ofα-synuclein ***,α-synuclein fibrils have been recently repo rted to release soluble and highly toxic oligomeric species,responsible for an immediate dysfunction in the recipient *** this review,we discuss the current knowledge about the plethora of mechanisms of cellular dysfunction caused byα-synuclein oligome rs and fibrils,both contributing to neurodegeneration in synucleinopathies.

关键词： amyloid aggregation neurodegeneration Parkinson’s disease protein aggregation protein misfolding

Peptide backbone-copper ring structure:A molecular insight into copper-induced amyloid toxicity

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Chinese Physics B 2022年第10期31卷 288-296页

作者： Jing Wang Hua Li Xiankai Jiang Bin Wu Jun Guo Xiurong Su Xingfei Zhou Yu Wang Geng Wang Heping Geng Zheng Jiang Fang Huang Gang Chen Chunlei Wang Haiping Fang Chenqi Xu Faculty of Science Ningbo UniversityNingbo 315211China National Center for protein Science Shanghai State Key Laboratory of Molecular BiologyInstitute of Biochemistry and Cell BiologyShanghai Institutes for Biological SciencesChinese Academy of SciencesShanghai 200031China School of Sciences Changzhou Institute of TechnologyChangzhou213032China Shanghai Synchrotron Radiation Facility Shanghai Institute of Applied PhysicsChinese Academy of SciencesShanghai 201800China Center for Bioengineering and Biotechnology China University of Petroleum(Huadong)Qingdao 266580China School of Physical Science and Technology ShanghaiTech UniversityShanghai 200031China Shanghai Advanced Research Institute Chinese Academy of SciencesShanghai 201210China School of Physics and National Engineering Research Center of Industrial Wastewater Detoxication and Resource Recovery East China University of Science and TechnologyShanghai 200031China School of Life Science and Technology ShanghaiTech UniversityShanghai 200031China

Copper ions can promote amyloid diseases that are associated with amyloid peptides, such as type 2 diabetes(T2D),Alzheimer's disease(AD), Parkinson's disease(PD), and amyotrophic lateral sclerosis(ALS). However, the underlying molecular mechanism remains obscure. Here we present that Cu^(2+)is able to specifically bind to the backbone of T2D related human islet amyloid polypeptide(hIAPP) by forming a ring structure, which causes the reduction of Cu^(2+)to Cu^(+) to produce reactive oxygen species(ROS) and the modulation of hIAPP aggregation. Nuclear magnetic resonance spectroscopy showed that Cu^(2+)bound to the backbone of a turn region, His18-Ser21, which is critical for hIAPP *** initio calculations and x-ray absorption fine structure analyses revealed that Cu^(2+)simultaneously bound with both the amide nitrogen and carbonyl oxygen on the peptide backbone, resulting in a ring structure, and causing the reduction of Cu^(2+)to Cu^(+) to form a hIAPP-Cu^(+) complex. 2′,7′-dichlorodihydrofluorescin diacetate fluorescence measurements further indicated that this complex led to enhanced ROS levels in rat insulinoma cells. Additionally, thioflavin T fluorescence and atomic force microscopy measurements denoted that the backbone-Cu ring structure largely modulated hIAPP aggregation,including the inhibition of hIAPP fibrillation and the promotion of peptide oligomerization. These findings shed new light on the molecular mechanism of Cu^(2+)-induced amyloid toxicity involving both the enhancement of ROS and the modulation of hIAPP aggregation.

关键词： interactions between metal ion and protein quantum chemistry calculation protein aggregation amyloid diseases

Cataract-causing mutation S228P promotes βB1-crystallin aggregation and degradation by separating two interacting loops in C-terminal domain

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protein & Cell 2016年第7期7卷 501-515页

作者： Liang-Bo Qi Li-Dan Hu Huihui Liu Hai-Yun Li Xiao-Yao Leng Yong-Bin Yan State Key Laboratory of Membrane Biology School of Life Sciences Tsinghua University Beijing 100084 China

β/γ-Crystallins are predominant structural proteins in the cytoplasm of lens fber cells and share a similar fold composing of four Greek-key motifs divided into two domains. Numerous cataract-causing mutations have been identified in various β/γ-crystallins, but the mech- anisms underlying cataract caused by most mutations remains uncharacterized. The S228P mutation in βB1- crystallin has been linked to autosomal dominant con- genital nuclear cataract. Here we found that the S228P mutant was prone to aggregate and degrade in both of the human and E. coli cells. The intracellular S228P aggregates could be redissolved by lanosterol. The S228P mutation modified the refolding pathway of βB1- crystallin by affecting the formation of the dimeric intermediate but not the monomeric intermediate. Compared with native βBl-crystallin, the refolded S228P protein had less packed structures, unquenched Trp fluorophores and increased hydrophobic exposure. The refolded S228P protein was prone to aggregate at the physiological temperature and decreased the protective effect of βB1-crystallin on βA3-crystallin. Molecular dynamic simulation studies indicated that the mutation decreased the subunit binding energy and modified the distribution of surface electrostatic potentials. More importantly, the mutation separated two interacting loops in the C-terminal domain, which shielded the hydrophobic core from solvent in native βB1-crystallin. These two interacting loops are highly conserved in both of the N- and C-terminal domains of all β/γ-crys- tallins. We propose that these two interacting loops play an important role in the folding and structural stability of β/γ-crystallin domains by protecting the hydrophobic core from solvent access.

关键词： β/γ-crystallin cataract-causing mutation,hydrophobic core protein aggregation protein folding