scholarly journals Evaluating Lipid‐Lowering Drug Targets for Parkinson's Disease Prevention with Mendelian Randomization

2020 ◽  
Vol 88 (5) ◽  
pp. 1043-1047
Author(s):  
Dylan M. Williams ◽  
Sara Bandres‐Ciga ◽  
Karl Heilbron ◽  
David Hinds ◽  
Alastair J. Noyce ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Disease Prevention ◽  
Drug Targets ◽  
Mendelian Randomization ◽  
Lipid Lowering ◽  
Lipid Lowering Drug ◽  
Lowering Drug

scholarly journals Finding genetically-supported drug targets for Parkinson’s disease using Mendelian randomization of the druggable genome

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Catherine S. Storm ◽  
Demis A. Kia ◽  
Mona M. Almramhi ◽  
Sara Bandres-Ciga ◽  
Chris Finan ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Drug Targets ◽  
Molecular Mechanisms ◽  
Mendelian Randomization ◽  
Disease Risk ◽  
Target Identification ◽  
Causal Effect ◽  
Age At Onset ◽  
Drug Repurposing

AbstractParkinson’s disease is a neurodegenerative movement disorder that currently has no disease-modifying treatment, partly owing to inefficiencies in drug target identification and validation. We use Mendelian randomization to investigate over 3,000 genes that encode druggable proteins and predict their efficacy as drug targets for Parkinson’s disease. We use expression and protein quantitative trait loci to mimic exposure to medications, and we examine the causal effect on Parkinson’s disease risk (in two large cohorts), age at onset and progression. We propose 23 drug-targeting mechanisms for Parkinson’s disease, including four possible drug repurposing opportunities and two drugs which may increase Parkinson’s disease risk. Of these, we put forward six drug targets with the strongest Mendelian randomization evidence. There is remarkably little overlap between our drug targets to reduce Parkinson’s disease risk versus progression, suggesting different molecular mechanisms. Drugs with genetic support are considerably more likely to succeed in clinical trials, and we provide compelling genetic evidence and an analysis pipeline to prioritise Parkinson’s disease drug development.

Abstract 19109: Low PCSK9 and LDL Cholesterol and Risk of Dementia, Parkinson’s Disease, and Epilepsy - A Mendelian Randomization Study

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Marianne Benn ◽  
Børge G Nordestgaard ◽  
Ruth Frikke-Schmidt ◽  
Anne Tybjærg-Hansen
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
General Population ◽  
Vascular Dementia ◽  
Genetic Variants ◽  
Mendelian Randomization ◽  
Alzheimer’S Dementia ◽  
Lipid Lowering ◽  
Alzheimer's Dementia ◽  
Risk Of Disease

Introduction: Low levels of low-density-lipoprotein cholesterol(LDL-C) due to statin use has been associated with reduced cognitive function. We aimed to assess whether low LDL-C due to genetic variation in the 3-hydroxy-3-methylglutaryl-CoA reductase(HMGCR; rs17238484) and proprotein convertase subtilisin kexin 9(PCSK9; rs11591147, rs148195424, rs562556, rs505151) genes, involved in LDL-C biosynthesis and metabolism, respectively, is associated with risk of Alzheimer’s dementia, vascular dementia, all dementia, Parkinson’s disease, and epilepsy in a general population off and on lipid lowering medication. Methods: We examined associations of plasma LDL-C with observational risk of disease; genetic variants with plasma LDL-C levels; and genetic variants and risk of disease as an indication of causality using a Mendelian randomization design in 92,068 participants off and 11,519 participants on lipid lowering medication from the Copenhagen General Population Study and the Copenhagen City Heart Study. Results: In observational analysis, risk of epilepsy was 98%(95% confidence interval: 32%-297%) higher in participants with an LDL-C <1.5mmol/L versus ≥3.0mmol/L. Low LDL-C was not associated with risk of Alzheimer’s dementia, vascular dementia, all dementia, and Parkinson’s disease. In causal genetic analyses, PCSK9 and HMGCR variants associated with 7.8% and 2.9% lower LDL-C. Genotypes were not associated with risk of Alzheimer’s dementia, vascular dementia, all dementia, Parkinson’s disease, or epilepsy. Conclusions: Using 103,587 individuals from the general population, we found that observationally low LDL-C level was associated with increased risk of epilepsy. Low LDL-C due to PCSK9 and HMGCR variants was not associated with Alzheimer’s dementia, vascular dementia, all dementia, Parkinson’s disease or epilepsy, and results does not support a causal role of low LDL-C in these diseases.

Berberine: A Promising Natural Isoquinoline Alkaloid for the Development of Hypolipidemic Drugs

2020 ◽  
Vol 20 (28) ◽  
pp. 2634-2647
Author(s):  
Dong-Dong Li ◽  
Pan Yu ◽  
Wei Xiao ◽  
Zhen-Zhong Wang ◽  
Lin-Guo Zhao
Keyword(s):  
Clinical Trials ◽  
Animal Models ◽  
Physicochemical Properties ◽  
Isoquinoline Alkaloid ◽  
Hypolipidemic Activity ◽  
Lipid Lowering ◽  
Lipid Lowering Drug ◽  
Lipid Lowering Agent ◽  
Lowering Drug ◽  
Hypolipidemic Drugs

: Berberine, as a representative isoquinoline alkaloid, exhibits significant hypolipidemic activity in both animal models and clinical trials. Recently, a large number of studies on the lipid-lowering mechanism of berberine and studies for improving its hypolipidemic activity have been reported, but for the most part, they have been either incomplete or not comprehensive. In addition, there have been a few specific reviews on the lipid-reducing effect of berberine. In this paper, the physicochemical properties, the lipid-lowering mechanism, and studies of the modification of berberine all are discussed to promote the development of berberine as a lipid-lowering agent. Subsequently, this paper provides some insights into the deficiencies of berberine in the study of lipid-lowering drug, and based on the situation, some proposals are put forward.

scholarly journals Causal Association between Periodontitis and Parkinson’s Disease: A Bidirectional Mendelian Randomization Study

Genes ◽  
2021 ◽  
Vol 12 (5) ◽  
pp. 772
Author(s):  
João Botelho ◽  
Vanessa Machado ◽  
José João Mendes ◽  
Paulo Mascarenhas
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Instrumental Variables ◽  
Mendelian Randomization ◽  
Association Studies ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Genetic Liability ◽  
Bidirectional Association

The latest evidence revealed a possible association between periodontitis and Parkinson’s disease (PD). We explored the causal relationship of this bidirectional association through two-sample Mendelian randomization (MR) in European ancestry populations. To this end, we used openly accessible data of genome-wide association studies (GWAS) on periodontitis and PD. As instrumental variables for periodontitis, seventeen single-nucleotide polymorphisms (SNPs) from a GWAS of periodontitis (1817 periodontitis cases vs. 2215 controls) and eight non-overlapping SNPs of periodontitis from an additional GWAS for validation purposes. Instrumental variables to explore for the reverse causation included forty-five SNPs from a GWAS of PD (20,184 cases and 397,324 controls). Multiple approaches of MR were carried-out. There was no evidence of genetic liability of periodontitis being associated with a higher risk of PD (B = −0.0003, Standard Error [SE] 0.0003, p = 0.26). The eight independent SNPs (B = −0.0000, SE 0.0001, p = 0.99) validated this outcome. We also found no association of genetically primed PD towards periodontitis (B = −0.0001, SE 0.0001, p = 0.19). These MR study findings do not support a bidirectional causal genetic liability between periodontitis and PD. Further GWAS studies are needed to confirm the consistency of these results.

A large remaining potential in lipid‐lowering drug treatment in the type 2 diabetes population – a Danish nationwide cohort study

2021 ◽  
Author(s):  
Hanan Amadid ◽  
Pernille F. Rønn ◽  
Maria BN. Dunbar ◽  
Jakob S. Knudsen ◽  
Bendix Carstensen ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Cohort Study ◽  
Drug Treatment ◽  
Lipid Lowering ◽  
Lipid Lowering Drug ◽  
Lowering Drug

scholarly journals Endoplasmic Reticulum Stress Regulators: New Drug Targets for Parkinson’s Disease

2021 ◽  
pp. 1-10
Author(s):  
Vera Kovaleva ◽  
Mart Saarma
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Endoplasmic Reticulum ◽  
Protein Folding ◽  
Er Stress ◽  
Protein Misfolding ◽  
Drug Targets ◽  
Dopamine Neurons ◽  
Drug Candidates ◽  
The Unfolded Protein Response

Parkinson’s disease (PD) pathology involves progressive degeneration and death of vulnerable dopamine neurons in the substantia nigra. Extensive axonal arborisation and distinct functions make this type of neurons particularly sensitive to homeostatic perturbations, such as protein misfolding and Ca2 + dysregulation. Endoplasmic reticulum (ER) is a cell compartment orchestrating protein synthesis and folding, as well as synthesis of lipids and maintenance of Ca2 +-homeostasis in eukaryotic cells. When misfolded proteins start to accumulate in ER lumen the unfolded protein response (UPR) is activated. UPR is an adaptive signalling machinery aimed at relieving of protein folding load in the ER. When UPR is chronic, it can either boost neurodegeneration and apoptosis or cause neuronal dysfunctions. We have recently discovered that mesencephalic astrocyte-derived neurotrophic factor (MANF) exerts its prosurvival action in dopamine neurons and in animal model of PD through the direct binding to UPR sensor inositol-requiring protein 1 alpha (IRE1α) and attenuation of UPR. In line with this, UPR targeting resulted in neuroprotection and neurorestoration in various preclinical PD animal models. Therefore, growth factors (GFs), possessing both neurorestorative activity and restoration of protein folding capacity are attractive as drug candidates for PD treatment especially their blood-brain barrier penetrating analogs and small molecule mimetics. In this review, we discuss ER stress as a therapeutic target to treat PD; we summarize the existing preclinical data on the regulation of ER stress for PD treatment. In addition, we point out the crucial aspects for successful clinical translation of UPR-regulating GFs and new prospective in GFs-based treatments of PD, focusing on ER stress regulation.

Plasma fibrinogen decrease by a lipid-lowering drug in healthy subjects

1992 ◽  
Vol 65 ◽  
pp. S174
Author(s):  
R. Paniccia ◽  
E. Chiarantini ◽  
M. Boddi ◽  
M. Filippini ◽  
M. Costanzo ◽  
...  
Keyword(s):  
Healthy Subjects ◽  
Plasma Fibrinogen ◽  
Lipid Lowering ◽  
Lipid Lowering Drug ◽  
Lowering Drug
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