Impact of high cholesterol in a Parkinson’s disease model: Prevention of lysosomal leakage versus stimulation of α-synuclein aggregation

Eriksson, Ida; Nath, Sangeeta; Bornefall, Per; Giraldo, Ana M. Villamil; Öllinger, Karin

doi:10.1016/j.ejcb.2017.01.002

Cited by 47 publications

(48 citation statements)

References 41 publications

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“…A previous study suggested that high cholesterol levels might attenuate the processes of neurodegeneration in PD via effects on peripheral organs or that low cholesterol levels could be markers of lifestyle changes influenced by nonmotor symptoms in the early stages of PD . At a molecular level, cholesterol stabilizes lysosomal membranes and prevents lysosomal permeabilization that leads to direct neural death . Then, statin therapy, which lowers low‐density lipoprotein cholesterol levels to approximately 70 to 130 mg/dL, can increase PD risk.…”

Section: Discussionmentioning

confidence: 99%

“…29 At a molecular level, cholesterol stabilizes lysosomal membranes and prevents lysosomal permeabilization that leads to direct neural death. 30 Then, statin therapy, which lowers lowdensity lipoprotein cholesterol levels to approximately 70 to 130 mg/dL, 31 can increase PD risk. Another potential mechanism for the increased risk of PD by statin includes that statins could reduce another potential neuroprotectant, such as coenzyme Q10.…”

Section: Discussionmentioning

confidence: 99%

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Association of statin use with Parkinson's disease: Dose–response relationship

2019

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Background There have been conflicting results on the association between statin use and Parkinson's disease (PD) incidence. Objectives This study investigated the association between time‐varying status of statin use and incidence of PD while considering the dose–response relationship and total cholesterol level. Methods Using the database of the Korean National Health Insurance Service from 2002 to 2015, we examined 76,043 subjects (≥60 years old) free of PD, dementia, and stroke at baseline. The dose of statin use was classified into the following four 6‐month categories (<180, 180‐365, 365‐540, and ≥540 days) for each 2‐year interval. The incidence of PD was identified by the prescription records for any anti‐PD medication with a diagnosis of PD. Results During 10 years of follow‐up, 1,427 PD cases occurred. Statin “ever use” was significantly associated with a high risk of PD incidence (adjusted hazard ratio = 1.28; 95% confidence interval = 1.12‐1.46) when compared with statin nonuse. In terms of a dose–response relationship, although a duration of statin use <365 days was associated with a higher risk of PD, the duration of statin use ≥365 days was not significantly associated with an increased risk of PD. Conclusions Statin use was associated with an elevated PD risk of PD, but long‐term and adherent statin use was not significantly associated with elevated PD risk. However, there was no evidence of benefit with any statin treatment related to PD risk. Our study suggests that there is a complex relationship among cholesterol level, statin use, and PD risk that warrants further studies. © 2019 International Parkinson and Movement Disorder Society

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Association of statin use with Parkinson's disease: Dose–response relationship

2019

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“…This evidence was reproduced in vitro, as a redistribution of lanosterol synthase from the ER to mitochondria in dopaminergic neurons exposed to 1-methyl-4phenylpyridinium (MPP + ) thus implying a survival effect via mitochondria (Lim et al, 2012). Furthermore, the cholesterol synthesis inhibitor lovastatin reduced MPP + -induced cell death by lowering ROS production without preventing the accumulation of cholesterol into lysosomes (Eriksson, Nath, Bornefall, Giraldo, & Ollinger, 2017 When this effect was mimicked by the cholesterol blocking agent U18666A, cell death was reduced,suggesting that lysosomal cholesterol accumulation may be an adaptive stress response.…”

Section: Lim Et Al Found That a Cholesterol Precursor Lanosterol Wasmentioning

confidence: 85%

“…When this effect was mimicked by the cholesterol blocking agent U18666A, cell death was reduced,suggesting that lysosomal cholesterol accumulation may be an adaptive stress response. Furthermore, the cholesterol synthesis inhibitor lovastatin reduced MPP + -induced cell death by lowering ROS production without preventing the accumulation of cholesterol into lysosomes (Eriksson, Nath, Bornefall, Giraldo, & Ollinger, 2017). This argues for further functions for mtChol.…”

Section: Lim Et Al Found That a Cholesterol Precursor Lanosterol Wasmentioning

confidence: 96%

Exploring mitochondrial cholesterol signalling for therapeutic intervention in neurological conditions

Desai

Campanella

2019

British J Pharmacology

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The pharmacological targeting of cholesterol levels continues to generate interest due to the undoubted success of therapeutic agents, such as statins, in extending life expectancy by modifying the prognosis of diseases associated with the impairment of lipid metabolism. Advances in our understanding of mitochondrial dysfunction in chronic age‐related diseases of the brain have disclosed an emerging role for mitochondrial cholesterol in their pathophysiology, thus delineating an opportunity to provide mechanistic insights and explore strategies of intervention. This review draws attention to novel signalling mechanisms in conditions linked with impaired metabolism associated with impaired handling of cholesterol and its oxidized forms (oxysterols) by mitochondria. By emphasizing the role of mitochondrial cholesterol in neurological diseases, we here call for novel approaches and new means of assessment. Linked Articles This article is part of a themed section on Mitochondrial Pharmacology: Featured Mechanisms and Approaches for Therapy Translation. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.22/issuetoc

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“…Increased entrance of oxysterol, the oxidized derivatives of cholesterol, into brain following hypercholesterolemia is a risk factor for neurodegeneration [9]. Increased α-synuclein aggregation, which plays a major role in PD pathogenesis, is observed when the neuronal cultures are grown in cholesterol-rich medium [10]. …”

Section: Introductionmentioning

confidence: 99%

1-Methyl-4-Phenylpyridinium-Induced Death of Differentiated SH-SY5Y Neurons Is Potentiated by Cholesterol

Raju¹,

Jaisankar

Borah

et al. 2017

Ann Neurosci

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Background/Aims: Hypercholesterolemia is recently considered a risk factor for Parkinson’s disease (PD), the most consistent neurodegenerative movement disorder. The study aimed to investigate the effect of exogenous cholesterol on 1-methyl-4-phenylpyridinium (MPP⁺) parkinsonian neurotoxin-induced cell death, loss of mitochondrial membrane potential, and dopaminergic deficiency in a cellular model of PD. Methods: Cholesterol (50 μM) when added in the culture media alone or in combination with MPP⁺ was studied in SH-SY5Y neuroblastoma cells. There were 4 groups that were studied; SH-SY5Y cells treated with vehicle (control), cells that were treated with 1 mM MPP⁺ (MPP⁺), or cholesterol (chol) or both (M + chol). The loss of cell survival was measured by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay. Dopamine depletion, microtubule-associated protein 2 (MAP-2), and tyrosine hydroxylase (TH)-positive neuronal loss were determined by HPLC-electrochemical detection and TH immunocytochemistry respectively. Mitochondrial membrane potential in cells stained by tetramethylrhodamine methyl ester dye was analysed by flow cytometry. Results: Cholesterol treatment potentiated a reduction of neuronal viability with loss of TH-positive neurons in cultures. MPP⁺-induced depletion of dopamine level in the post-mitotic MAP-2 immunoreactive neurons and loss of mitochondrial membrane potential were also heightened by cholesterol. Conclusion: Apparently, changes in neuronal cholesterol content significantly influenced the neurotoxicity and the direct mitochondrial mechanisms involved in MPP⁺-induced cell death. Our observations demonstrate that high cholesterol incorporated into the differentiated human neuroblastoma cells worsened dopaminergic neuronal survivability through increased depolarization of mitochondrial membrane potential, which is a known mechanism of dopaminergic cell death by MPP⁺. The present findings support the hypothesis that hypercholesterolemia could be a risk factor for PD.

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Impact of high cholesterol in a Parkinson’s disease model: Prevention of lysosomal leakage versus stimulation of α-synuclein aggregation

Cited by 47 publications

References 41 publications

Association of statin use with Parkinson's disease: Dose–response relationship

Association of statin use with Parkinson's disease: Dose–response relationship

Exploring mitochondrial cholesterol signalling for therapeutic intervention in neurological conditions

1-Methyl-4-Phenylpyridinium-Induced Death of Differentiated SH-SY5Y Neurons Is Potentiated by Cholesterol

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