title: Impact of high cholesterol in a Parkinson's disease model: Prevention of lysosomal leakage versus stimulation of α-synuclein aggregation.
abstract: Parkinson's disease is characterized by accumulation of intraneuronal cytoplasmic inclusions, Lewy bodies, which mainly consist of aggregated α-synuclein. Controversies exist as to whether high blood cholesterol is a risk factor for the development of the disease and whether statin treatment could have a protective effect. Using a model system of BE(2)-M17 neuroblastoma cells treated with the neurotoxin 1-methyl-4-phenylpyridinium (MPP+), we found that MPP+-induced cell death was accompanied by cholesterol accumulation in a lysosomal-like pattern in pre-apoptotic cells. To study the effects of lysosomal cholesterol accumulation, we increased lysosomal cholesterol through pre-treatment with U18666A and found delayed leakage of lysosomal contents into the cytosol, which reduced cell death. This suggests that increased lysosomal cholesterol is a stress response mechanism to protect lysosomal membrane integrity in response to early apoptotic stress. However, high cholesterol also stimulated the accumulation of α-synuclein. Treatment with the cholesterol-lowering drug lovastatin reduced MPP+-induced cell death by inhibiting the production of reactive oxygen species, but did not prevent lysosomal cholesterol increase nor affect α-synuclein accumulation. Our study indicates a dual role of high cholesterol in Parkinson's disease, in which it acts both as a protector against lysosomal membrane permeabilization and as a stimulator of α-synuclein accumulation.
authors.affiliation: Experimental Pathology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden. Electronic address: ida.eriksson@liu.se.
authors.forename: Ida
authors.initials: I
authors.lastname: Eriksson
authors.affiliation: Experimental Pathology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden. Electronic address: sangeeta.nath@liu.se.
authors.forename: Sangeeta
authors.initials: S
authors.lastname: Nath
authors.affiliation: Experimental Pathology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden. Electronic address: perbo650@student.liu.se.
authors.forename: Per
authors.initials: P
authors.lastname: Bornefall
authors.affiliation: Experimental Pathology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden. Electronic address: ana.villamil.giraldo@liu.se.
authors.forename: Ana Maria Villamil
authors.initials: AM
authors.lastname: Giraldo
authors.affiliation: Experimental Pathology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden. Electronic address: karin.ollinger@liu.se.
authors.forename: Karin
authors.initials: K
authors.lastname: Öllinger
mesh_terms: D000924:Anticholesteremic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000502:physiology; D002784:Cholesterol / Q000378:metabolism*; D006801:Humans; D008148:Lovastatin / Q000494:pharmacology; D008247:Lysosomes / Q000378:metabolism*; D010300:Parkinson Disease / Q000378:metabolism* / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D051844:alpha-Synuclein / Q000378:metabolism*
chemical_list: D000924:Anticholesteremic Agents; D017382:Reactive Oxygen Species; D051844:alpha-Synuclein; D002784:Cholesterol; D008148:Lovastatin
keywords: 1-Methyl-4-phenylpyridinium (MPP(+)); Cholesterol; Lovastatin; Lysosome; Parkinson’s disease; Reactive oxygen species (ROS); α-Synuclein