scholarly journals Differences in network controllability and regional gene expression underlie hallucinations in Parkinson’s disease

Brain ◽  
2020 ◽  
Vol 143 (11) ◽  
pp. 3435-3448
Author(s):  
Angeliki Zarkali ◽  
Peter McColgan ◽  
Mina Ryten ◽  
Regina Reynolds ◽  
Louise-Ann Leyland ◽  
...  
Keyword(s):  
Gene Expression ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Protein Localization ◽  
Expression Patterns ◽  
Structural Connectivity ◽  
Brain Regions ◽  
Brain Network ◽  
Visual Hallucinations ◽  
Regional Gene

Abstract Visual hallucinations are common in Parkinson’s disease and are associated with poorer prognosis. Imaging studies show white matter loss and functional connectivity changes with Parkinson’s visual hallucinations, but the biological factors underlying selective vulnerability of affected parts of the brain network are unknown. Recent models for Parkinson’s disease hallucinations suggest they arise due to a shift in the relative effects of different networks. Understanding how structural connectivity affects the interplay between networks will provide important mechanistic insights. To address this, we investigated the structural connectivity changes that accompany visual hallucinations in Parkinson’s disease and the organizational and gene expression characteristics of the preferentially affected areas of the network. We performed diffusion-weighted imaging in 100 patients with Parkinson’s disease (81 without hallucinations, 19 with visual hallucinations) and 34 healthy age-matched controls. We used network-based statistics to identify changes in structural connectivity in Parkinson’s disease patients with hallucinations and performed an analysis of controllability, an emerging technique that allows quantification of the influence a brain region has across the rest of the network. Using these techniques, we identified a subnetwork of reduced connectivity in Parkinson’s disease hallucinations. We then used the Allen Institute for Brain Sciences human transcriptome atlas to identify regional gene expression patterns associated with affected areas of the network. Within this network, Parkinson’s disease patients with hallucinations showed reduced controllability (less influence over other brain regions), than Parkinson’s disease patients without hallucinations and controls. This subnetwork appears to be critical for overall brain integration, as even in controls, nodes with high controllability were more likely to be within the subnetwork. Gene expression analysis of gene modules related to the affected subnetwork revealed that down-weighted genes were most significantly enriched in genes related to mRNA and chromosome metabolic processes (with enrichment in oligodendrocytes) and upweighted genes to protein localization (with enrichment in neuronal cells). Our findings provide insights into how hallucinations are generated, with breakdown of a key structural subnetwork that exerts control across distributed brain regions. Expression of genes related to mRNA metabolism and membrane localization may be implicated, providing potential therapeutic targets.

scholarly journals A pH-eQTL interaction at the RIT2-SYT4 Parkinson's disease risk locus in the substantia nigra

2020 ◽  
Author(s):  
Sejal Patel ◽  
Derek Howard ◽  
Leon French
Keyword(s):  
Gene Expression ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Substantia Nigra ◽  
Human Brain ◽  
Disease Risk ◽  
Brain Regions ◽  
Dopamine Neurons ◽  
Postmortem Human Brain ◽  
Increased Risk

BACKGROUND: Parkinson's disease (PD) causes severe motor and cognitive disabilities that result from the progressive loss of dopamine neurons in the substantia nigra. The rs12456492 variant in the RIT2 gene has been repeatedly associated with increased risk for Parkinson's disease. From a transcriptomic perspective, a meta-analysis found that RIT2 gene expression is correlated with pH in the human brain. OBJECTIVE: To assess pH associations at the RIT2-SYT4 locus. METHODS: Linear models to examine two datasets that assayed rs12456492, gene expression, and pH in the postmortem human brain. RESULTS: Using the BrainEAC dataset, we replicate the positive correlation between RIT2 gene expression and pH in the human brain. Furthermore, we found that the relationship between expression and pH is influenced by rs12456492. When tested across ten brain regions, this interaction is specifically found in the substantia nigra. A similar association was found for the co-localized SYT4 gene. In addition, SYT4 associations are stronger in a combined model with both genes, and the SYT4 interaction appears to be specific to males. In the GTEx dataset, the pH associations involving rs12456492 and expression of either SYT4 and RIT2 was not seen. This null finding may be due to the short postmortem intervals (PMI) of the GTEx tissue samples. In the BrainEAC data, we tested the effect of PMI and only observed the interactions in the longer PMI samples. CONCLUSIONS: These previously unknown associations suggest novel mechanistic roles for rs12456492, RIT2, and SYT4 in the regulation of pH in the substantia nigra.

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 Dementia risk in Parkinson’s disease is associated with interhemispheric connectivity loss and determined by regional gene expression

2020 ◽  
Vol 28 ◽  
pp. 102470
Author(s):  
Angeliki Zarkali ◽  
Peter McColgan ◽  
Mina Ryten ◽  
Regina H. Reynolds ◽  
Louise-Ann Leyland ◽  
...  
Keyword(s):  
Gene Expression ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Dementia Risk ◽  
Interhemispheric Connectivity ◽  
Regional Gene

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 Neurodegeneration and neuroinflammation are linked, but independent of α-synuclein inclusions, in a seeding/spreading mouse model of Parkinson’s disease

2020 ◽  
Author(s):  
Pierre Garcia ◽  
Wiebke Jürgens-Wemheuer ◽  
Oihane Uriarte ◽  
Kristopher J Schmit ◽  
Annette Masuch ◽  
...  
Keyword(s):  
Gene Expression ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Gene Expression Profiling ◽  
Expression Profiling ◽  
Active Role ◽  
Brain Regions ◽  
Alpha Synuclein ◽  
Intracerebral Injection ◽  
Inclusion Formation

AbstractA key process of neurodegeneration in Parkinson’s disease (PD) is the transneuronal spreading of α-synuclein. Alpha-synuclein is a presynaptic protein that is implicated in the pathogenesis of PD and other synucleinopathies, where it forms, upon intracellular aggregation, pathological inclusions. Other hallmarks of PD include neurodegeneration and microgliosis in susceptible brain regions. Whether it is primarily transneuronal spreading of α-synuclein particles, inclusion formation, or other mechanisms, such as inflammation, that cause neurodegeneration in PD is unclear. We used spreading/aggregation of α-synuclein induced by intracerebral injection of α-synuclein preformed fibrils into the mouse brain to address this question. We performed quantitative histological analysis for α-synuclein inclusions, neurodegeneration, and microgliosis in different brain regions, and a gene expression profiling of the ventral midbrain, at two different timepoints after disease induction. We observed significant neurodegeneration and microgliosis in brain regions not only with, but also without α-synuclein inclusions. We also observed prominent microgliosis in injured brain regions that did not correlate with neurodegeneration nor with inclusion load. In longitudinal gene expression profiling experiments, we observed early and unique alterations linked to microglial mediated inflammation that preceded neurodegeneration, indicating an active role of microglia in inducing neurodegeneration. Our observations indicate that α-synuclein inclusion formation is not the major driver in the early phases of PD-like neurodegeneration, but that diffusible, oligomeric α-synuclein species, which induce unusual microglial reactivity, play a key role in this process. Our findings uncover new features of α-synuclein induced pathologies, in particular microgliosis, and point to the necessity of a broader view of the process of “prion-like spreading” of that protein.

scholarly journals Narcolepsy in Parkinson's disease with insulin resistance

F1000Research ◽  
2020 ◽  
Vol 9 ◽  
pp. 1361
Author(s):  
Alisha Chunduri ◽  
Wim E. Crusio ◽  
Anna Delprato
Keyword(s):  
Insulin Resistance ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Immune System ◽  
Expression Patterns ◽  
Brain Regions ◽  
Intervention Strategies ◽  
Comorbid Disorders ◽  
Integrative Genomics ◽  
Dorsal Thalamus

Background: Parkinson’s disease (PD) is characterized by its progression of motor-related symptoms such as tremors, rigidity, slowness of movement, and difficulty with walking and balance. Comorbid conditions in PD individuals include insulin resistance (IR) and narcolepsy-like sleep patterns. The intersecting sleep symptoms of both conditions include excessive daytime sleepiness, hallucinations, insomnia, and falling into REM sleep more quickly than an average person. Understanding of the biological basis and relationship of these comorbid disorders with PD may help with early detection and intervention strategies to improve quality of life. Methods: In this study, an integrative genomics and systems biology approach was used to analyze gene expression patterns associated with PD, IR, and narcolepsy in order to identify genes and pathways that may shed light on how these disorders are interrelated. A correlation analysis with known genes associated with these disorders (LRRK2, HLA-DQB1, and HCRT) was used to query microarray data corresponding to brain regions known to be involved in PD and narcolepsy. This includes the hypothalamus, dorsal thalamus, pons, and subcoeruleus nucleus. Risk factor genes for PD, IR, and narcolepsy were also incorporated into the analysis. Results: The PD and narcolepsy signaling networks are connected through insulin and immune system pathways. Important genes and pathways that link PD, narcolepsy, and IR are CACNA1C, CAMK1D, BHLHE41, HMGB1, and AGE-RAGE. Conclusions: We have identified the genetic signatures that link PD with its comorbid disorders, narcolepsy and insulin resistance, from the convergence and intersection of dopaminergic, insulin, and immune system related signaling pathways. These findings may aid in the design of early intervention strategies and treatment regimes for non-motor symptoms in PD patients as well as individuals with diabetes and narcolepsy.

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.

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.

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