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Impact of high cholesterol in a Parkinsons disease model: Prevention of lysosomal leakage versus stimulation of alpha-synuclein aggregation
Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
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2017 (English)In: European Journal of Cell Biology, ISSN 0171-9335, E-ISSN 1618-1298, Vol. 96, no 2, 99-109 p.Article in journal (Refereed) Published
Abstract [en]

Parkinsons disease is characterized by accumulation of intraneuronal cytoplasmic inclusions, Lewy bodies, which mainly consist of aggregated alpha-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 alpha-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 alpha-synuclein accumulation. Our study indicates a dual role of high cholesterol in Parkinsons disease, in which it acts both as a protector against lysosomal membrane permeabilization and as a stimulator of alpha-synuclein accumulation. (C) 2017 Elsevier GmbH. All rights reserved.

Place, publisher, year, edition, pages
ELSEVIER GMBH, URBAN & FISCHER VERLAG , 2017. Vol. 96, no 2, 99-109 p.
Keyword [en]
Cholesterol; alpha-Synuclein; Parkinsons disease; Lovastatin; Lysosome; 1-Methyl-4-phenylpyridinium (MPP+); Reactive oxygen species (ROS)
National Category
Cell Biology
Identifiers
URN: urn:nbn:se:liu:diva-142445DOI: 10.1016/j.ejcb.2017.01.002ISI: 000412150200002PubMedID: 28109635OAI: oai:DiVA.org:liu-142445DiVA: diva2:1153639
Note

Funding Agencies|Swedish Research Council; Parkinson Foundation at Linkoping University; Konung Gustaf V och Drottning Victorias Frimurarestiftelse

Available from: 2017-10-31 Created: 2017-10-31 Last updated: 2017-10-31

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Eriksson, IdaNath, SangeetaBornefall, PerVillamil Giraldo, Ana MariaÖllinger, Karin
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Division of Cell BiologyFaculty of Medicine and Health SciencesDivision of Neuro and Inflammation ScienceDepartment of Clinical Pathology and Clinical Genetics
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