scholarly journals Genome-wide epigenetic analyses in Japanese immigrant plantation workers with Parkinson’s Disease and exposure to organochlorines reveal glial genes and pathways involved in neurotoxicity

2019 ◽  
Author(s):  
Rodney C.P. Go ◽  
Michael J Corley ◽  
George Webster Ross ◽  
Helen Petrovich ◽  
Kamal H Masaki ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Dna Methylation ◽  
Parkinson's Disease ◽  
Epidemiological Studies ◽  
Postmortem Brain ◽  
Genome Wide ◽  
Proinflammatory Responses ◽  
The Central Nervous System ◽  
Pathway Analyses ◽  
Humanmethylation450k Beadchip

Abstract Background: Parkinson’s Disease (PD) is a disease of the central nervous system that progressively affects the motor system. Epidemiological studies have provided evidence that exposure to agriculture-related occupations or agrichemicals elevate a person’s risk for PD. Here, we sought to examine the possible epigenetic changes associated with working on a plantation on Oahu, HI and/or exposure to organochlorines (OGC) in PD cases. Results: We measured genome-wide DNA methylation using the Illumina Infinium HumanMethylation450K BeadChip array in matched peripheral blood and postmortem brain biospecimens in PD cases (n=21) assessed for years of plantation work and presence of organochlorines in brain tissue. The comparison of 10+ to 0 years of plantation work exposure detected 7 and 123 differentially methylated loci (DML) in brain and blood DNA, respectively ( P <0.0001). The comparison of cases with 4+ to 0-2 detectable levels of OGC, identified 8 and 18 DML in brain and blood DNA, respectively ( P <0.0001). Pathway analyses revealed links to key neurotoxic and neuropathologic pathways related to impaired immune and proinflammatory responses as well as impaired clearance of damaged proteins, as found in the predominantly glial cell population in these environmental exposure-related PD cases. Conclusions : These results suggest that distinct DNA methylation biomarker profiles related to environmental exposures in PD cases with previous exposure can be found in both brain and blood.

scholarly journals Genome-wide epigenetic analyses in Japanese immigrant plantation workers with Parkinson’s Disease and exposure to organochlorines reveal possible involvement of glial genes and pathways involved in neurotoxicity

2020 ◽  
Author(s):  
Rodney C.P. Go ◽  
Michael J Corley ◽  
George Webster Ross ◽  
Helen Petrovich ◽  
Kamal H Masaki ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Dna Methylation ◽  
Parkinson's Disease ◽  
Epidemiological Studies ◽  
Postmortem Brain ◽  
Genome Wide ◽  
Proinflammatory Responses ◽  
The Central Nervous System ◽  
Pathway Analyses ◽  
Humanmethylation450k Beadchip

Abstract Background: Parkinson’s Disease (PD) is a disease of the central nervous system that progressively affects the motor system. Epidemiological studies have provided evidence that exposure to agriculture-related occupations or agrichemicals elevate a person’s risk for PD. Here, we sought to examine the possible epigenetic changes associated with working on a plantation on Oahu, HI and/or exposure to organochlorines (OGC) in PD cases. Results: We measured genome-wide DNA methylation using the Illumina Infinium HumanMethylation450K BeadChip array in matched peripheral blood and postmortem brain biospecimens in PD cases (n=20) assessed for years of plantation work and presence of organochlorines in brain tissue. The comparison of 10+ to 0 years of plantation work exposure detected 7 and 123 differentially methylated loci (DML) in brain and blood DNA, respectively (P<0.0001). The comparison of cases with 4+ to 0-2 detectable levels of OGC, identified 8 and 18 DML in brain and blood DNA, respectively (P <0.0001). Pathway analyses revealed links to key neurotoxic and neuropathologic pathways related to impaired immune and proinflammatory responses as well as impaired clearance of damaged proteins, as found in the predominantly glial cell population in these environmental exposure-related PD cases.Conclusions: These results suggest that distinct DNA methylation biomarker profiles related to environmental exposures in PD cases with previous exposure can be found in both brain and blood.

scholarly journals Butyrate and related epigenetic changes link Parkinson's disease to inflammatory bowel disease and depressive symptoms

2021 ◽  
Author(s):  
Aoji Xie ◽  
Elizabeth Ensink ◽  
Peipei Li ◽  
Juozas Gordevicius ◽  
Lee L. Marshall ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Dna Methylation ◽  
Parkinson's Disease ◽  
Depressive Symptoms ◽  
Gut Microbiome ◽  
Whole Blood ◽  
Blood Samples ◽  
Targeted Bisulfite Sequencing ◽  
Genome Wide ◽  
Whole Blood Samples

Background The gut microbiome and its metabolites can impact brain health and are altered in Parkinson's disease (PD) patients. It has been recently demonstrated that PD patients have reduced fecal levels of the potent epigenetic modulator butyrate and its bacterial producers. Here, we investigate whether the changes in the gut microbiome and associated metabolites are linked to PD symptoms and epigenetic markers in leucocytes and neurons. Methods Stool, whole blood samples, and clinical data were collected from 55 PD patients and 55 controls. We performed DNA methylation analysis on whole blood samples and analyzed the results in relation to fecal short-chain fatty acid concentrations and microbiota composition. In another cohort, prefrontal cortex neurons were isolated from control and PD brains. We identified the genome-wide DNA methylation by targeted bisulfite sequencing. Results We show that lower fecal butyrate and reduced Roseburia, Romboutsia, and Prevotella counts are linked to depressive symptoms in PD patients. Genes containing butyrate-associated methylation sites include PD risk genes and significantly overlap with sites epigenetically altered in PD blood leucocytes, predominantly neutrophils, and in brain neurons, relative to controls. Moreover, butyrate-associated methylated-DNA (mDNA) regions in PD overlap with those altered in gastrointestinal, autoimmune, and psychiatric diseases.

scholarly journals DNA methylation changes associated with Parkinson’s disease progression: outcomes from the first longitudinal genome-wide methylation analysis in blood

Epigenetics ◽  
2019 ◽  
Vol 14 (4) ◽  
pp. 365-382 ◽  
Author(s):  
Adrienne Henderson-Smith ◽  
Kathleen M. Fisch ◽  
Jianping Hua ◽  
Ganqiang Liu ◽  
Eugenia Ricciardelli ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Dna Methylation ◽  
Parkinson's Disease ◽  
Disease Progression ◽  
Methylation Analysis ◽  
Genome Wide

scholarly journals Parkinson’s Disease-Associated, Sex-specific Changes in DNA Methylation at PARK7 (DJ-1), ATXN1, SLC17A6, NR4A2, and PTPRN2 in Cortical Neurons

2021 ◽  
Author(s):  
Joseph Kochmanski ◽  
Nathan C. Kuhn ◽  
Alison I. Bernstein
Keyword(s):  
Parkinson’S Disease ◽  
Dna Methylation ◽  
Parkinson's Disease ◽  
Cortical Neurons ◽  
Disease Risk ◽  
Neuronal Population ◽  
Tissue Samples ◽  
Genome Wide ◽  
Dna Modifications ◽  
The Relationship

AbstractEvidence for epigenetic regulation playing a role in Parkinson’s disease (PD) is growing, particularly for DNA modifications. Approximately 90% of PD cases are due to a complex interaction between age, genes, and environmental factors, and epigenetic marks are thought to mediate the relationship between aging, genetics, the environment, and disease risk. To date, there are a small number of published genome-wide studies of DNA modifications in PD, but none accounted for cell-type or sex in their analyses. Given the hetereogeneity of bulk brain tissue samples and known sex differences in PD risk, progression, and severity, these are critical variables to account for. In this first genome-wide analysis of DNA methylation in an enriched neuronal population from PD post-mortem parietal cortex, we report sex-specific PD-associated methylation changes in PARK7 (DJ-1), SLC17A6 (VGLUT2), PTPRN2 (IA-2β), NR4A2 (NURR1), and other genes involved in developmental pathways, neurotransmitter packaging and release, and axon and neuron projection guidance.

scholarly journals Genome‐wide association studies of LRRK2 modifiers of Parkinson's disease

2021 ◽  
Author(s):  
Dongbing Lai ◽  
Babak Alipanahi ◽  
Pierre Fontanillas ◽  
Tae‐Hwi Schwantes‐An ◽  
Jan Aasly ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Association Studies ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Genome Wide

scholarly journals Single-Cell RNA Sequencing in Parkinson’s Disease

Biomedicines ◽  
2021 ◽  
Vol 9 (4) ◽  
pp. 368
Author(s):  
Shi-Xun Ma ◽  
Su Bin Lim
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Single Cell ◽  
Rna Sequencing ◽  
Rna Degradation ◽  
Postmortem Brain ◽  
Cell Type ◽  
New Findings ◽  
Postmortem Brain Tissue ◽  
Technical Challenges

Single-cell and single-nucleus RNA sequencing (sc/snRNA-seq) technologies have enhanced the understanding of the molecular pathogenesis of neurodegenerative disorders, including Parkinson’s disease (PD). Nonetheless, their application in PD has been limited due mainly to the technical challenges resulting from the scarcity of postmortem brain tissue and low quality associated with RNA degradation. Despite such challenges, recent advances in animals and human in vitro models that recapitulate features of PD along with sequencing assays have fueled studies aiming to obtain an unbiased and global view of cellular composition and phenotype of PD at the single-cell resolution. Here, we reviewed recent sc/snRNA-seq efforts that have successfully characterized diverse cell-type populations and identified cell type-specific disease associations in PD. We also examined how these studies have employed computational and analytical tools to analyze and interpret the rich information derived from sc/snRNA-seq. Finally, we highlighted important limitations and emerging technologies for addressing key technical challenges currently limiting the integration of new findings into clinical practice.

scholarly journals The Baseline Structure of the Enteric Nervous System and Its Role in Parkinson’s Disease

Life ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 732
Author(s):  
Gianfranco Natale ◽  
Larisa Ryskalin ◽  
Gabriele Morucci ◽  
Gloria Lazzeri ◽  
Alessandro Frati ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Nervous System ◽  
Enteric Nervous System ◽  
Gi Tract ◽  
Multiple Control ◽  
Fine Control ◽  
The Central Nervous System ◽  
Degenerative Alterations ◽  
Comprehensive Classification

The gastrointestinal (GI) tract is provided with a peculiar nervous network, known as the enteric nervous system (ENS), which is dedicated to the fine control of digestive functions. This forms a complex network, which includes several types of neurons, as well as glial cells. Despite extensive studies, a comprehensive classification of these neurons is still lacking. The complexity of ENS is magnified by a multiple control of the central nervous system, and bidirectional communication between various central nervous areas and the gut occurs. This lends substance to the complexity of the microbiota–gut–brain axis, which represents the network governing homeostasis through nervous, endocrine, immune, and metabolic pathways. The present manuscript is dedicated to identifying various neuronal cytotypes belonging to ENS in baseline conditions. The second part of the study provides evidence on how these very same neurons are altered during Parkinson’s disease. In fact, although being defined as a movement disorder, Parkinson’s disease features a number of degenerative alterations, which often anticipate motor symptoms. Among these, the GI tract is often involved, and for this reason, it is important to assess its normal and pathological structure. A deeper knowledge of the ENS is expected to improve the understanding of diagnosis and treatment of Parkinson’s disease.

Inflammatory Mechanisms in Parkinson’s Disease: From Pathogenesis to Targeted Therapies

2021 ◽  
pp. 107385842199226
Author(s):  
Stellina Y. H. Lee ◽  
Nathanael J. Yates ◽  
Susannah J. Tye
Keyword(s):  
Parkinson’S Disease ◽  
Central Nervous System ◽  
Parkinson's Disease ◽  
Nervous System ◽  
Immune Cells ◽  
Critical Factor ◽  
Neurodegenerative Process ◽  
Inflammatory Processes ◽  
The Central Nervous System ◽  
Novel Target

Inflammation is a critical factor contributing to the progressive neurodegenerative process observed in Parkinson’s disease (PD). Microglia, the immune cells of the central nervous system, are activated early in PD pathogenesis and can both trigger and propagate early disease processes via innate and adaptive immune mechanisms such as upregulated immune cells and antibody-mediated inflammation. Downstream cytokines and gene regulators such as microRNA (miRNA) coordinate later disease course and mediate disease progression. Biomarkers signifying the inflammatory and neurodegenerative processes at play within the central nervous system are of increasing interest to clinical teams. To be effective, such biomarkers must achieve the highest sensitivity and specificity for predicting PD risk, confirming diagnosis, or monitoring disease severity. The aim of this review was to summarize the current preclinical and clinical evidence that suggests that inflammatory processes contribute to the initiation and progression of neurodegenerative processes in PD. In this article, we further summarize the data about main inflammatory biomarkers described in PD to date and their potential for regulation as a novel target for disease-modifying pharmacological strategies.

scholarly journals α-Synuclein BAC transgenic mice exhibit RBD-like behaviour and hyposmia: a prodromal Parkinson’s disease model

Brain ◽  
2019 ◽  
Vol 143 (1) ◽  
pp. 249-265 ◽  
Author(s):  
Tomoyuki Taguchi ◽  
Masashi Ikuno ◽  
Mari Hondo ◽  
Laxmi Kumar Parajuli ◽  
Katsutoshi Taguchi ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Transgenic Mice ◽  
Rem Sleep ◽  
Genome Wide Association Study ◽  
Artificial Chromosome ◽  
Genome Wide Association ◽  
Genome Wide ◽  
A Genome ◽  
Familial Parkinson’S Disease

Abstract Parkinson’s disease is one of the most common movement disorders and is characterized by dopaminergic cell loss and the accumulation of pathological α-synuclein, but its precise pathogenetic mechanisms remain elusive. To develop disease-modifying therapies for Parkinson’s disease, an animal model that recapitulates the pathology and symptoms of the disease, especially in the prodromal stage, is indispensable. As subjects with α-synuclein gene (SNCA) multiplication as well as point mutations develop familial Parkinson’s disease and a genome-wide association study in Parkinson’s disease has identified SNCA as a risk gene for Parkinson’s disease, the increased expression of α-synuclein is closely associated with the aetiology of Parkinson’s disease. In this study we generated bacterial artificial chromosome transgenic mice harbouring SNCA and its gene expression regulatory regions in order to maintain the native expression pattern of α-synuclein. Furthermore, to enhance the pathological properties of α-synuclein, we inserted into SNCA an A53T mutation, two single-nucleotide polymorphisms identified in a genome-wide association study in Parkinson’s disease and a Rep1 polymorphism, all of which are causal of familial Parkinson’s disease or increase the risk of sporadic Parkinson’s disease. These A53T SNCA bacterial artificial chromosome transgenic mice showed an expression pattern of human α-synuclein very similar to that of endogenous mouse α-synuclein. They expressed truncated, oligomeric and proteinase K-resistant phosphorylated forms of α-synuclein in the regions that are specifically affected in Parkinson’s disease and/or dementia with Lewy bodies, including the olfactory bulb, cerebral cortex, striatum and substantia nigra. Surprisingly, these mice exhibited rapid eye movement (REM) sleep without atonia, which is a key feature of REM sleep behaviour disorder, at as early as 5 months of age. Consistent with this observation, the REM sleep-regulating neuronal populations in the lower brainstem, including the sublaterodorsal tegmental nucleus, nuclei in the ventromedial medullary reticular formation and the pedunculopontine nuclei, expressed phosphorylated α-synuclein. In addition, they also showed hyposmia at 9 months of age, which is consistent with the significant accumulation of phosphorylated α-synuclein in the olfactory bulb. The dopaminergic neurons in the substantia nigra pars compacta degenerated, and their number was decreased in an age-dependent manner by up to 17.1% at 18 months of age compared to wild-type, although the mice did not show any related locomotor dysfunction. In conclusion, we created a novel mouse model of prodromal Parkinson’s disease that showed RBD-like behaviour and hyposmia without motor symptoms.

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