Dysregulated LRRK2 Signaling in Response to Endoplasmic Reticulum Stress Leads to Dopaminergic Neuron Degeneration in C. elegans 英文参考文献.docVIP

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Dysregulated LRRK2 Signaling in Response to Endoplasmic Reticulum Stress Leads to Dopaminergic Neuron Degeneration in C. elegans 英文参考文献.doc

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Dysregulated LRRK2 Signaling in Response to Endoplasmic Reticulum Stress Leads to Dopaminergic Neuron Degeneration in C. elegans 英文参考文献

DysregulatedLRRK2SignalinginResponseto EndoplasmicReticulumStressLeadstoDopaminergic NeuronDegenerationinC.elegans YiyuanYuan1,PengxiuCao1,MarkA.Smith2,KristopherKramp1,YingHuang1,NaokiHisamoto4, KunihiroMatsumoto4,MariaHatzoglou3,HuiJin1,ZhaoyangFeng1,5* 1DepartmentofPharmacology,SchoolofMedicine,CaseWesternReserveUniversity,Cleveland,Ohio,UnitedStatesofAmerica,2DepartmentofPathology,Schoolof Medicine,CaseWesternReserveUniversity,Cleveland,Ohio,UnitedStatesofAmerica,3DepartmentofNutrition,SchoolofMedicine,CaseWesternReserveUniversity, Cleveland,Ohio,UnitedStatesofAmerica,4DepartmentofMolecularBiology,GraduateSchoolofScience,InstituteforAdvancedResearch,NagoyaSolution-Oriented ResearchforScienceandTechnology,JapanScienceandTechnologyCorporation,Chikusa-ku,Nagoya,Japan, 5DepartmentofPhysiology,CollegeofMedicine,Xi’an JiaotongUniversity,Xi’an,Shaanxi,China Abstract Mutationofleucine-richrepeatkinase2(LRRK2)istheleadinggeneticcauseofParkinson’sDisease(PD),manifestedasage- dependentdopaminergicneurodegeneration,buttheunderlyingmolecularmechanismsremainunclear.Multiplerolesof LRRK2maycontributetodopaminergicneurodegeneration.Endoplasmicreticulum(ER)stresshasalsobeenlinkedtoPD pathogenesis,butitsinteractivemechanismwithPDgeneticfactorsislargelyunknown.Here,weusedC.elegans ,human neuroblastoma cells and murine cortical neurons to determine the role of LRRK2 in maintaining dopaminergic neuron viability.WefoundthatLRRK2actstoprotectneuroblastomacellsandC.elegansdopaminergicneuronsfromthetoxicityof 6-hydroxydopamineand/orhumana-synuclein,possiblythroughthep38pathway,bysupportingupregulationofGRP78,a keycellsurvivalmoleculeduringERstress.ApathogenicLRRK2mutant(G2019S),however,causedchronicp38activation that led to death of murine neurons and age-related dopaminergic-specific neurodegeneration in nematodes. These observationsestablishacriticalfunctionallinkbetweenLRRK2andERstress. Citation: Yuan Y, Cao P, Smith MA, Kramp K, Huang Y, et al. (2011) Dysregulated LRRK2 Sign