scholarly journals Genetic differences in the aryl hydrocarbon receptor and CYP1A2 affect susceptibility to developmental polychlorinated biphenyl exposure in mice: Relevance to studies of human neurological disorders

2017 ◽  
Author(s):  
Kelsey Klinefelter ◽  
Molly Kromme Hooven ◽  
Chloe Bates ◽  
Breann T. Colter ◽  
Alexandra Dailey ◽  
...  
Keyword(s):  
Gene Expression ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Aryl Hydrocarbon Receptor ◽  
Expression Patterns ◽  
Health Concern ◽  
Coplanar Pcbs ◽  
Aryl Hydrocarbon ◽  
The Brain ◽  
Pcb Exposure

AbstractPolychlorinated biphenyls (PCBs) are persistent organic pollutants that remain a human health concern with the discovery of new sources of contamination and ongoing bioaccumulation and biomagnification. Children exposed during early brain development are at highest risk of neurological deficits, but there is some evidence that high PCB exposure in adults increases the risk of Parkinson’s disease. Our previous studies found allelic differences in the aryl hydrocarbon receptor and cytochrome P450 1A2 (CYP1A2) affect susceptibility to developmental PCB exposure, resulting in cognitive deficits and motor dysfunction. High-affinity AhrbCyp1a2(-/-) mice were most susceptible compared with poor-affinity AhrdCyp1a2(-/-) and wild type AhrbCyp1a2(+/+) mice. Our follow-up studies assessed biochemical, histological and gene expression changes to identify the brain regions and pathways affected. We also measured PCB and metabolite levels in multiple tissues to determine if genotype altered toxicokinetics. We found evidence of AHR-mediated immune suppression with reduced thymus and spleen weights and significantly reduced thyroxine at P14. In the brain, the greatest changes were seen in the cerebellum where a foliation defect was over-represented in Cyp1a2(-/-) mice. In contrast, we found no difference in tyrosine hydroxylase immuno-staining in the striatum. Gene expression patterns varied across the three genotypes, but there was clear evidence of AHR activation. Distribution of parent PCB congeners also varied by genotype with strikingly high levels of PCB 77 in poor-affinity AhrdCyp1a2(-/-) while AhrbCyp1a2(+/+) mice effectively sequestered coplanar PCBs in the liver. Together, our data suggest that the AHR pathway plays a role in developmental PCB neurotoxicity, but we found little evidence that developmental exposure is a risk factor for Parkinson’s disease.

scholarly journals C. elegans genetic background modifies the core transcriptional response in an α-synuclein model of Parkinson’s disease

2018 ◽  
Author(s):  
Yiru A. Wang ◽  
Basten L. Snoek ◽  
Mark G. Sterken ◽  
Joost A.G. Riksen ◽  
Jana J. Stastna ◽  
...  
Keyword(s):  
Gene Expression ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Genetic Background ◽  
Expression Patterns ◽  
Transcriptional Response ◽  
Global Gene Expression ◽  
C Elegans ◽  
The Core ◽  
Repair Mechanisms

AbstractAccumulation of protein aggregates is a major cause of Parkinson’s disease (PD), a progressive neurodegenerative condition that is one of the most common causes of dementia. Transgenic Caenorhabditis elegans worms expressing the human synaptic protein α-synuclein show inclusions of aggregated protein and replicate the defining pathological hallmarks of PD. It is however not known how PD progression and pathology differs among individual genetic backgrounds. Here, we compared gene expression patterns, and investigated the phenotypic consequences of transgenic α-synuclein expression in five different C. elegans genetic backgrounds. Transcriptome analysis indicates that the effects of -synuclein expression on pathways associated with nutrient storage, lipid transportation and ion exchange depend on the genetic background. The gene expression changes we observe suggest that a range of phenotypes will be affected by α-synuclein expression. We experimentally confirm this, showing that the transgenic lines generally show delayed development, reduced lifespan, and an increased rate of matricidal hatching. These phenotypic effects coincide with the core changes in gene expression, linking developmental arrest, mobility, metabolic and cellular repair mechanisms to α-synuclein expression. Together, our results show both genotype-specific effects and core alterations in global gene expression and in phenotype in response to -synuclein. We conclude that the PD effects are substantially modified by the genetic background, illustrating that genetic background mechanisms should be elucidated to understand individual variation in PD.

scholarly journals Transcriptomic signatures associated with regional cortical thickness changes in Parkinson’s disease

2020 ◽  
Author(s):  
Arlin Keo ◽  
Oleh Dzyubachyk ◽  
Jeroen van der Grond ◽  
Jacobus J. van Hilten ◽  
Marcel J. T. Reinders ◽  
...  
Keyword(s):  
Gene Expression ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cortical Thickness ◽  
Expression Patterns ◽  
Brain Atlas ◽  
Cortical Atrophy ◽  
Integrated Analysis ◽  
Gene Expression Patterns ◽  
Mitochondrial Translation

AbstractCortical atrophy is a common manifestation in Parkinson’s disease, particularly in later disease stages. Here, we investigated patterns of cortical thickness using T1-weighted anatomical MRI data of 149 Parkinson’s disease patients and 369 controls. To elucidate the molecular underpinnings of cortical thickness changes in Parkinson’s disease, we performed an integrated analysis of brain-wide healthy transcriptomic data from the Allen Human Brain Atlas and neuroimaging features. For this purpose, we used partial least squares regression to identify gene expression patterns correlated with cortical thickness changes. In addition, we identified gene expression patterns underlying the relationship between cortical thickness and clinical domains of Parkinson’s disease. Our results show that genes whose expression in the healthy brain is associated with cortical thickness changes in Parkinson’s disease are enriched in biological pathways related to sumoylation, regulation of mitotic cell cycle, mitochondrial translation, DNA damage responses, and ER-Golgi traffic. The associated pathways were highly related to each other and all belong to cellular maintenance mechanisms. The expression of genes within most pathways was negatively correlated with cortical thickness changes, showing higher expression in regions associated with decreased cortical thickness (atrophy). On the other hand, sumoylation pathways were positively correlated with cortical thickness changes, showing higher expression in regions with increased cortical thickness (hypertrophy). Our findings suggest that alterations in the balanced interplay of these mechanisms play a role in changes of cortical thickness in Parkinson’s disease and possibly influence motor and cognitive functions.

Contrasting gene expression patterns induced by levodopa and pramipexole treatments in the rat model of Parkinson's disease

2016 ◽  
Vol 101 ◽  
pp. 576-589 ◽  
Author(s):  
Irene R. Taravini ◽  
Celia Larramendy ◽  
Gimena Gomez ◽  
Mariano D. Saborido ◽  
Floor Spaans ◽  
...  
Keyword(s):  
Gene Expression ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Rat Model ◽  
Expression Patterns ◽  
Gene Expression Patterns

scholarly journals DNA Methylation and Expression Profiles of Whole Blood in Parkinson’s Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Adrienne R. Henderson ◽  
Qi Wang ◽  
Bessie Meechoovet ◽  
Ashley L. Siniard ◽  
Marcus Naymik ◽  
...  
Keyword(s):  
Gene Expression ◽  
Parkinson’S Disease ◽  
Dna Methylation ◽  
Parkinson's Disease ◽  
Transcription Factor ◽  
Whole Blood ◽  
Expression Profiles ◽  
Expression Patterns ◽  
Motor Deficits ◽  
Age Related

Parkinson’s disease (PD) is the second most common age-related neurodegenerative disease. It is presently only accurately diagnosed at an advanced stage by a series of motor deficits, which are predated by a litany of non-motor symptoms manifesting over years or decades. Aberrant epigenetic modifications exist across a range of diseases and are non-invasively detectable in blood as potential markers of disease. We performed comparative analyses of the methylome and transcriptome in blood from PD patients and matched controls. Our aim was to characterize DNA methylation and gene expression patterns in whole blood from PD patients as a foundational step toward the future goal of identifying molecular markers that could predict, accurately diagnose, or track the progression of PD. We found that differentially expressed genes (DEGs) were involved in the processes of transcription and mitochondrial function and that PD methylation profiles were readily distinguishable from healthy controls, even in whole-blood DNA samples. Differentially methylated regions (DMRs) were functionally varied, including near transcription factor nuclear transcription factor Y subunit alpha (NFYA), receptor tyrosine kinase DDR1, RING finger ubiquitin ligase (RNF5), acetyltransferase AGPAT1, and vault RNA VTRNA2-1. Expression quantitative trait methylation sites were found at long non-coding RNA PAX8-AS1 and transcription regulator ZFP57 among others. Functional epigenetic modules were highlighted by IL18R1, PTPRC, and ITGB2. We identified patterns of altered disease-specific DNA methylation and associated gene expression in whole blood. Our combined analyses extended what we learned from the DEG or DMR results alone. These studies provide a foundation to support the characterization of larger sample cohorts, with the goal of building a thorough, accurate, and non-invasive molecular PD biomarker.

scholarly journals Transcriptomic Signatures Associated With Regional Cortical Thickness Changes in Parkinson’s Disease

2021 ◽  
Vol 15 ◽  
Author(s):  
Arlin Keo ◽  
Oleh Dzyubachyk ◽  
Jeroen van der Grond ◽  
Jacobus J. van Hilten ◽  
Marcel J. T. Reinders ◽  
...  
Keyword(s):  
Gene Expression ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cortical Thickness ◽  
Expression Patterns ◽  
Brain Atlas ◽  
Cortical Atrophy ◽  
Integrated Analysis ◽  
Gene Expression Patterns ◽  
Mitochondrial Translation

Cortical atrophy is a common manifestation in Parkinson’s disease (PD), particularly in advanced stages of the disease. To elucidate the molecular underpinnings of cortical thickness changes in PD, we performed an integrated analysis of brain-wide healthy transcriptomic data from the Allen Human Brain Atlas and patterns of cortical thickness based on T1-weighted anatomical MRI data of 149 PD patients and 369 controls. For this purpose, we used partial least squares regression to identify gene expression patterns correlated with cortical thickness changes. In addition, we identified gene expression patterns underlying the relationship between cortical thickness and clinical domains of PD. Our results show that genes whose expression in the healthy brain is associated with cortical thickness changes in PD are enriched in biological pathways related to sumoylation, regulation of mitotic cell cycle, mitochondrial translation, DNA damage responses, and ER-Golgi traffic. The associated pathways were highly related to each other and all belong to cellular maintenance mechanisms. The expression of genes within most pathways was negatively correlated with cortical thickness changes, showing higher expression in regions associated with decreased cortical thickness (atrophy). On the other hand, sumoylation pathways were positively correlated with cortical thickness changes, showing higher expression in regions with increased cortical thickness (hypertrophy). Our findings suggest that alterations in the balanced interplay of these mechanisms play a role in changes of cortical thickness in PD and possibly influence motor and cognitive functions.

Gene expression patterns for GDNF and its receptors in the human putamen affected by Parkinson's disease: A real-time PCR study

2006 ◽  
Vol 252 (1-2) ◽  
pp. 160-166 ◽  
Author(s):  
Cristina M. Bäckman ◽  
Lufei Shan ◽  
Ya Jun Zhang ◽  
Barry J. Hoffer ◽  
Sherry Leonard ◽  
...  
Keyword(s):  
Gene Expression ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Real Time ◽  
Real Time Pcr ◽  
Expression Patterns ◽  
Gene Expression Patterns

Comparison Analysis of Gene Expression Patterns between Sporadic Alzheimer's and Parkinson's Disease

2007 ◽  
Vol 12 (4) ◽  
pp. 291-311 ◽  
Author(s):  
Edna Grünblatt ◽  
Nicole Zander ◽  
Jasmin Bartl ◽  
Li Jie ◽  
Camelia-Maria Monoranu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Expression Patterns ◽  
Gene Expression Patterns ◽  
Comparison Analysis
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