Genetic Regulation of α-Synuclein mRNA Expression in Various Human Brain Tissues 英文参考文献.docVIP

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Genetic Regulation of α-Synuclein mRNA Expression in Various Human Brain Tissues 英文参考文献.doc

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Genetic Regulation of α-Synuclein mRNA Expression in Various Human Brain Tissues 英文参考文献

GeneticRegulationofa-SynucleinmRNAExpressionin VariousHumanBrainTissues ColtonLinnertz1,LauraSaucier1,DongliangGe1,KennethD.Cronin1,JamesR.Burke2,3,JeffreyN. Browndyke3,ChristineM.Hulette3,KathleenA.Welsh-Bohmer3,OrnitChiba-Falek1,2,3* 1Institute for Genome Sciences Policy, Duke University Medical Center, Durham, North Carolina, United States ofAmerica, 2Division of Neurology, Department of Medicine,DukeUniversityMedicalCenter,Durham,NorthCarolina,UnitedStatesofAmerica,3JosephandKathleenBryanAlzheimer’sDiseaseResearchCenter,Duke UniversityMedicalCenter,Durham,NorthCarolina,UnitedStatesofAmerica Abstract GeneticvariabilityacrosstheSNCAlocushasbeenrepeatedlyassociatedwithsusceptibilitytosporadicParkinson’sdisease (PD). Accumulated evidence emphasizes the importance of SNCA dosage and expression levels in PD pathogenesis. HoweverwhethergeneticvariabilityintheSNCAgenemodulatestherisktodevelopsporadicPDviaregulationofSNCA expressionremainedelusive.WestudiedtheeffectofPDrisk-associatedvariantsatSNCA59and39regionsonSNCA-mRNA levelsinvivoin228humanbrainsamplesfromthreestructuresdifferentiallyvulnerabletoPDpathology(substantia-nigra, temporal- and frontal-cortex) obtained from 144 neurologically normal cadavers. The extensively characterized PD- associatedpromoterpolymorphism,Rep1,hadaneffectonSNCA-mRNAlevels.Homozygousgenotypeofthe‘protective’, Rep1-259bpallele,wasassociatedwithlowerlevelsofSNCA-mRNArelativetoindividualsthatcarriedatleastonecopyof thePD-riskassociatedalleles,amountingtoanaveragedecreaseof,40%and.50%intemporal-cortexandsubstantia- nigra,respectively.Furthermore,SNPstaggingtheSNCA39-untranslated-regionalsoshowedeffectsonSNCA-mRNAlevels in both the temporal-cortex and the substantia-nigra, although, in contrast to Rep1, the ‘decreased-risk’ alleles were correlated with increased SNCA-mRNA levels. Similar to Rep1 findings, no difference in SNCA-mRNA level was seen with different SNCA 39SNP alleles in the frontal-cortex, indicating there is brain-region speci