Alteration of POLDIP3 Splicing Associated with Loss of Function of TDP-43 in Tissues Affected with ALS 英文参考文献.docVIP

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Alteration of POLDIP3 Splicing Associated with Loss of Function of TDP-43 in Tissues Affected with ALS 英文参考文献.doc

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Alteration of POLDIP3 Splicing Associated with Loss of Function of TDP-43 in Tissues Affected with ALS 英文参考文献

AlterationofPOLDIP3SplicingAssociatedwithLossof FunctionofTDP-43inTissuesAffectedwithALS AtsushiShiga1,TomohikoIshihara2,AkinoriMiyashita3,MisakiKuwabara2,TaisukeKato2, NorihiroWatanabe4,AkieYamahira4,ChigusaKondo2,AkioYokoseki2,MasuhiroTakahashi4, RyozoKuwano3,AkiyoshiKakita5,MasatoyoNishizawa2,HitoshiTakahashi1,OsamuOnodera6* 1DepartmentofPathology,BrainResearchInstitute,NiigataUniversity,Niigata,Japan,2DepartmentofNeurology,BrainResearchInstitute,NiigataUniversity,Niigata, Japan,3DepartmentofMolecularGenetics,GenomeScienceBranch,CenterforBioresource-BasedResearches,BrainResearchInstitute,NiigataUniversity,Niigata,Japan, 4LaboratoryofHematologyandOncology,GraduateSchoolofHealthSciences,NiigataUniversity,Niigata,Japan,5DepartmentofPathologicalNeuroscience,Resource BranchforBrainDiseaseResearch,BrainResearchInstitute,NiigataUniversity,Niigata,Japan,6DepartmentofMolecularNeuroscience,ResourceBranchforBrainDisease Research,BrainResearchInstitute,NiigataUniversity,Niigata,Japan Abstract Amyotrophiclateralsclerosis(ALS)isanadult-onsetneurodegenerativediseasecausedbyselectivelossofmotorneurons. IntheALSmotorneurons,TARDNA-bindingproteinof43kDa(TDP-43)isdislocatedfromthenucleustocytoplasmand forms inclusions, suggesting that loss of a nuclear function of TDP-43 may underlie the pathogenesis of ALS. TDP-43 functions in RNA metabolism include regulation of transcription, mRNA stability, and alternative splicing of pre-mRNA. However,afunctionofTDP-43intissueaffectedwithALShasnotbeenelucidated.Wesoughttoidentifythemolecular indicatorsreflectingonaTDP-43function.Usingexonarrayanalysis,weobservedaremarkablealterationofsplicinginthe polymerasedeltainteractingprotein3(POLDIP3)asaresultofthedepletionofTDP-43expressionintwotypesofcultured cells.InthecellstreatedwithTDP-43siRNA,wild-typePOLDIP3(variant-1)decreasedandPOLDIP3lackingexon3(variant-2) increased. The RNA binding ability of TDP-43 was necessary for inclusion of POLDIP3 exon 3. Moreover, we found an increment of POLDIP3 v