CLN3p Impacts Galactosylceramide Transport, RaftCnN3p对半乳糖神经酰胺转运的影响 形态和脂类含量

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1、0031-3998/08/6306-0625Vol.63,No.6,2008PEDIATRICRESEARCHPrintedinU.S.A.Copyright©2008InternationalPediatricResearchFoundation,Inc.CLN3pImpactsGalactosylceramideTransport,RaftMorphology,andLipidContentELENARUSYN,TALALMOUSALLEM,DIXIE-ANNPERSAUD-SAWIN,SAR

2、AMILLER,ANDROSE-MARYN.BOUSTANYDepartmentsofNeurobiology[E.R.,T.M.,D.-A.P.-S.,R.-M.N.B.],Pathology[S.M.],DukeUniversityMedicalCenter,Durham,NorthCarolina27710;Abu-HaidarNeuroscienceInstitute[R.-M.N.B.],AmericanUniversityofBeirut,11072020,Beirut,Lebanon

3、ABSTRACT:Juvenileneuronalceroidlipofuscinosis(JNCL)belongsCLN3pishighlyconserved.Causesofcelldeathinthetotheneuronalceroidlipofuscinosescharacterizedbyblindness/brain/retinaremaincontroversial.CLN3pimpartsantiapop-seizures/motor/cognitivedeclineandear

4、lydeath.JNCLiscausedbytoticpropertiestoneurons/cells(4)andregulatesautophagyCLN3genemutationsthatnegativelymodulatecellgrowth/apoptosis.(5).CLN3-deficientcellshaveacceleratedapoptosisandal-CLN3protein(CLN3p)localizestoGolgi/Rab4-/Rab11-positiveendo-ter

5、edceramide/sphingomyelinlevelsthatcorrectwiththesomesandlipidrafts,andharborsagalactosylceramide(GalCer)lipidadditionofCLN3p.CLN3mRNA/proteinareoverexpressedraft-bindingdomain.GoalsareprovingCLN3pparticipatesinGalCertransportfromGolgitorafts,andGalCer

6、deficitsnegativelyaffectcellincancercells(6).growth/apoptosis.GalCer/mutantCLN3pareretainedinGolgi,withCLN3pisplacedinHEK/HeLaendosomes(7),yeastvacu-CLN3prescuingGalCerdeficitsinrafts.DiminishingGalCerinnormaloles,mouseretinalcellmitochondria(8),neurona

7、lsynapto-cellsbyGalCersynthasesiRNAnegativelyaffectscellgrowth/somes/synapses(9),nucleiiofratneurons(10),andGolgi/apoptosis.GalCerrestoresJNCLcellgrowth.WTCLN3pbindsGalCer,plasmamembrane(PM)inHeLa/fibroblasts/COS-7cells(11).butnotmutantCLN3p.Sphingolip

8、idcontentofrafts/GolgiisperturbedWild-type(WT)CLN3plocalizestoGolgi/PMandtrafficsviawithdiminishedGalCerinraftsandaccumulationinGolgi.CLN3-earlyrecyclingRab4/Rab11-endosomesfromGolgitolipiddeficientraftvesicularstructuresaresmallbytransmissionel