Sensitivity to Lysosome-Dependent Cell Death Is Directly Regulated by Lysosomal Cholesterol Content 英文参考文献.docVIP
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Sensitivity to Lysosome-Dependent Cell Death Is Directly Regulated by Lysosomal Cholesterol Content 英文参考文献
SensitivitytoLysosome-DependentCellDeathIsDirectly
RegulatedbyLysosomalCholesterolContent
HannaAppelqvist1*,LinneaSandin1,KarinBjo¨rnstro¨m2,3,PaulSaftig4,BrettGarner5,6,KarinOllinger¨ 1,7,
KatarinaKa?gedal1
1ExperimentalPathology,DepartmentofClinicalandExperimentalMedicine,FacultyofHealthSciences,Linko¨pingUniversity,Linko¨ping,Sweden,2Anaesthesiology,
DepartmentofMedicalandHealthSciences,FacultyofHealthSciences,Linko¨pingUniversity,Linko¨ping,Sweden,3DepartmentofAnaesthesiologyUHL,CountyCouncil
ofO¨stergo¨tland,Linko¨ping,Sweden,4BiochemicalInstitute,Christian-Albrechts-UniversityKiel,Kiel,Germany,5IllawarraHealthandMedicalResearchInstitute,University
ofWollongong,Wollongong,Australia,6SchoolofBiologicalSciences,UniversityofWollongong,Wollongong,Australia,7DepartmentofClinicalPathologyandClinical
Genetics,CountyCouncilofO¨stergo¨tland,Linko¨ping,Sweden
Abstract
Alterationsinlipidhomeostasisareimplicatedinseveralneurodegenerativediseases,althoughthemechanismsresponsible
arepoorlyunderstood.Weevaluatedtheimpactofcholesterolaccumulation,inducedbyU18666A,quinacrineormutations
in the cholesterol transporting Niemann-Pick disease type C1 (NPC1) protein, on lysosomal stability and sensitivity to
lysosome-mediated cell death. We found that neurons with lysosomal cholesterol accumulation were protected from
oxidative stress-induced apoptosis. In addition, human fibroblasts with cholesterol-loaded lysosomes showed higher
lysosomalmembranestabilitythancontrols.Previousstudieshaveshownthatcholesterolaccumulationisaccompaniedby
the storage of lipids such as sphingomyelin, glycosphingolipids and sphingosine and an up regulation of lysosomal
associatedmembraneprotein-2(LAMP-2),whichmayalsoinfluencelysosomalstability.However,inthisstudytheuseof
myriocinandLAMPdeficientfibroblastsexcludedthesefactorsasresponsiblefortherescuingeffectandinsteadsuggested
thatprimarilylysosomalcholesterolcontentdetermineDthecellularsensitivitytotoxicinsults.Furtherstrengtheningthis
c
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