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

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.

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Effect of zonisamide co-administration with levodopa on global gene expression in the striata of rats with Parkinson’s disease

Biochemical and Biophysical Research Communications ◽

10.1016/j.bbrc.2012.10.067 ◽

2012 ◽

Vol 428 (3) ◽

pp. 401-404 ◽

Cited By ~ 4

Author(s):

Yuto Ueda ◽

Shoko Tokashiki ◽

Ai Kanemaru ◽

Toshio Kojima

Keyword(s):

Gene Expression ◽

Parkinson’S Disease ◽

Parkinson's Disease ◽

Global Gene Expression

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The universal non-neuronal nature of Parkinson's disease: A theory

10.7287/peerj.preprints.1314v1 ◽

2015 ◽

Author(s):

André Valente ◽

Altynay Adilbayeva ◽

Tursonjan Tokay ◽

Albert Rizvanov

Keyword(s):

Gene Expression ◽

Parkinson’S Disease ◽

Parkinson's Disease ◽

Mitochondrial Dna ◽

Late Onset ◽

Clinical Signs ◽

Global Gene Expression ◽

Neuron Death ◽

Hematopoietic Stem ◽

Hematopoietic Stem Cell Niche

Various recent developments of relevance to Parkinson's disease (PD) are discussed and integrated into a comprehensive hypothesis on the nature, origin and inter-cellular mode of propagation of late-onset sporadic PD. We propose to define sporadic PD as a characteristic pathological deviation in the global gene expression program of a cell: the PD expression-state, or PD-state for short. Although a universal cell-generic state, the PD-state deviation would be particularly damaging in a neuronal context, ultimately leading to neuron death and the ensuing observed clinical signs. We review why age accumulated damage caused by oxidative stress in mitochondria could be the trigger for a primordial cell to shift to the PD-state. We put forward hematopoietic cells could be the first to acquire the PD-state, at hematopoiesis, from the disruption in reactive oxygen species (ROS) homeostasis that arises with age in the hematopoietic stem-cell niche. We argue why, nonetheless, such a process is unlikely to explain the shift to the PD-state of all the subsequently affected cells in a patient, thus indicating the existence of a distinct mechanism of propagation of the PD-state. We highlight recent findings on the intercellular exchange of mitochondrial DNA and the ability of mitochondrial DNA to modulate the cellular global gene expression state and propose this could form the basis for the intercellular propagation of the PD-state.

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The Universal Non-Neuronal Nature of Parkinson's Disease: A Theory

Central Asian Journal of Global Health ◽

10.5195/cajgh.2016.231 ◽

2016 ◽

Vol 5 (1) ◽

Cited By ~ 2

Author(s):

Andre X.C.N. Valente ◽

Altynai Adilbayeva ◽

Tursonjan Tokay ◽

Albert Rizvanov

Keyword(s):

Gene Expression ◽

Parkinson’S Disease ◽

Parkinson's Disease ◽

Mitochondrial Dna ◽

Clinical Signs ◽

Global Gene Expression ◽

Neuron Death ◽

Hematopoietic Stem ◽

Hematopoietic Stem Cell Niche ◽

Published Evidence

Parkinson's disease (PD) is one of the most common neurodegenerative disorders, yet the etiology of the majority of its cases remains unknown. In this manuscript, relevant published evidence is interpreted and integrated into a comprehensive hypothesis on the nature, origin, and inter-cellular mode of propagation of sporadic PD. We propose to characterize sporadic PD as a pathological deviation in the global gene expression program of a cell: the PD expression-state, or PD-state for short. A universal cell-generic state, the PD-state deviation would be particularly damaging in a neuronal context, ultimately leading to neuron death and the ensuing observed clinical signs. We review why ageing associated accumulated damage caused by oxidative stress in mitochondria could be the trigger for a primordial cell to shift to the PD-state. We propose that hematopoietic cells could be the first to acquire the PD-state, at hematopoiesis, from the disruption in reactive oxygen species homeostasis that arises with age in the hematopoietic stem-cell niche. We argue that cellular ageing is nevertheless unlikely to explain the shift to the PD-state of all the subsequently affected cells in a patient, thus indicating the existence of a distinct mechanism of cellular propagation of the PD-state. We highlight recently published findings on the inter-cellular exchange of mitochondrial DNA and the ability of mitochondrial DNA to modulate the cellular global gene expression state and propose this could form the basis for the inter-cellular transmission of the PD-state.

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

Neuropharmacology ◽

10.1016/j.neuropharm.2015.04.018 ◽

2016 ◽

Vol 101 ◽

pp. 576-589 ◽

Cited By ~ 4

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

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

Frontiers in Genetics ◽

10.3389/fgene.2021.640266 ◽

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.

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

Frontiers in Neuroscience ◽

10.3389/fnins.2021.733501 ◽

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.

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

10.1101/2020.06.19.158808 ◽

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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