Experimental and Computational Analysis of Polyglutamine-Mediated Cytotoxicity 英文参考文献.docVIP

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Experimental and Computational Analysis of Polyglutamine-Mediated Cytotoxicity 英文参考文献.doc

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Experimental and Computational Analysis of Polyglutamine-Mediated Cytotoxicity 英文参考文献

ExperimentalandComputationalAnalysisof Polyglutamine-MediatedCytotoxicity MatthewY.Tang1,2,CaroleJ.Proctor3,JohnWoulfe1,2,DouglasA.Gray1,2,3 * 1OttawaHospital Research Institute, Ottawa,Ontario, Canada, 2Department ofBiochemistry, Microbiology andImmunology, University ofOttawa, Ottawa, Ontario, Canada, 3Centre for Integrated Systems Biology of Ageing and Nutrition, Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, United Kingdom Abstract Expandedpolyglutamine(polyQ)proteinsareknowntobethecausativeagentsofanumberofhumanneurodegenerative diseasesbutthemolecularbasisoftheircytoxicityisstillpoorlyunderstood.PolyQtractsmayimpedetheactivityofthe proteasome, and evidence from single cell imaging suggests that the sequestration of polyQ into inclusion bodies can reducetheproteasomalburdenandpromotecellsurvival,atleastintheshortterm.Thepresenceofmisfoldedproteinalso leadstoactivationofstresskinasessuchasp38MAPK,whichcanbecytotoxic.Therelationshipsofthesesystemsarenot wellunderstood.Wehaveusedfluorescentreportersystemsimagedinlivingcells,andstochasticcomputermodelingto exploretherelationshipsofpolyQ,p38MAPKactivation,generationofreactiveoxygenspecies(ROS),proteasomeinhibition, andinclusionbodyformation.IncellsexpressingapolyQproteininclusion,bodyformationwasprecededbyproteasome inhibitionbutcytotoxicitywasgreatlyreducedbyadministrationofap38MAPKinhibitor.Computersimulationssuggested thatwithoutthegenerationofROS,theproteasomeinhibitionandactivationofp38MAPKwouldhavesignificantlyreduced toxicity.Ourdatasuggestaviciouscycleofstresskinaseactivationandproteasomeinhibitionthatisultimatelylethalto cells. There was close agreement between experimental data and the predictions of a stochastic computer model, supportingacentralroleforproteasomeinhibitionandp38MAPKactivationininclusionbodyformationandROS-mediated celldeath. Citation: Tang MY, Proctor CJ, Woulfe J, Gray DA (2010) Experimental and Computational Analysis of Polyglutamine-Mediated Cytotoxicity.