Cell-Autonomous Death of Cerebellar Purkinje Neurons with Autophagy in Niemann-Pick Type C Disease 英文参考文献.docVIP

Cell-AutonomousDeathofCerebellar PurkinjeNeuronswithAutophagy inNiemann-PickTypeCDisease Dennis C.Ko, Ljiljana Milenkovic, Steven M.Beier, Hermogenes Manuel, JoAnn Buchanan, Matthew P.Scott* DepartmentsofDevelopmentalBiology,Genetics,andBioengineering,HowardHughesMedicalInstitute,StanfordUniversitySchoolofMedicine,Stanford,California,United StatesofAmerica Niemann-PicktypeCisaneurodegenerativelysosomalstoragedisordercausedbymutationsineitheroftwogenes, npc1andnpc2.CellslackingNpc1,whichisatransmembraneproteinrelatedtotheHedgehogreceptorPatched,or Npc2, which is a secreted cholesterol-binding protein, have aberrant organelle trafficking and accumulate large quantities of cholesterol and other lipids. Though the Npc proteins are produced by all cells, cerebellar Purkinje neurons are especially sensitive to loss of Npc function. Since Niemann-Pick type C disease involves circulating moleculessuchassterolsandsteroidsandarobustinflammatoryresponsewithinthebrainparenchyma,itiscrucialto determine whether external factors affect the survival of Purkinje cells (PCs). We investigated the basis of neurodegenerationinchimericmicethathavefunctionalnpc1inonlysomecells.Deathofmutantnpc1cellswasnot preventedbyneighboringwild-typecells,andwild-typePCswerenotpoisonedbysurroundingmutantnpc1cells.PCs undergoing cell-autonomous degeneration have features consistent with autophagic cell death. Chimeric mice exhibitedaremarkabledelayandreductionofwastingandataxiadespitetheirsubstantialamountofmutanttissue anddyingcells,revealingarobustmechanismthatpartiallycompensatesformassivePCdeath. Citation:KoDC,MilenkovicL,BeierSM,ManuelH,BuchananJ,etal.(2005)Cell-autonomousdeathofcerebellarPurkinjeneuronswithautophagyinNiemann-PicktypeC disease.PLoSGenet1(1):e7. which harbor spontaneous mutations in npc1 [6]. The most striking and well-documented histological change in npc1 Introduction Niemann-Pick type C (NPC) is a devastating autosomal recessive neurodegenerative disorder characterized by the