scholarly journals Insights into the multifaceted role of circular RNAs: implications for Parkinson’s disease pathogenesis and diagnosis

2022 ◽  
Vol 8 (1) ◽  
Author(s):  
Epaminondas Doxakis
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Clinical Manifestations ◽  
Alpha Synuclein ◽  
Circular Rnas ◽  
Age Related ◽  
And Function ◽  
The Brain

AbstractParkinson’s disease (PD) is a complex, age-related, neurodegenerative disease whose etiology, pathology, and clinical manifestations remain incompletely understood. As a result, care focuses primarily on symptoms relief. Circular RNAs (circRNAs) are a large class of mostly noncoding RNAs that accumulate with aging in the brain and are increasingly shown to regulate all aspects of neuronal and glial development and function. They are generated by the spliceosome through the backsplicing of linear RNA. Although their biological role remains largely unknown, they have been shown to regulate transcription and splicing, act as decoys for microRNAs and RNA binding proteins, used as templates for translation, and serve as scaffolding platforms for signaling components. Considering that they are stable, diverse, and detectable in easily accessible biofluids, they are deemed promising biomarkers for diagnosing diseases. CircRNAs are differentially expressed in the brain of patients with PD, and growing evidence suggests that they regulate PD pathogenetic processes. Here, the biogenesis, expression, degradation, and detection of circRNAs, as well as their proposed functions, are reviewed. Thereafter, research linking circRNAs to PD-related processes, including aging, alpha-synuclein dysregulation, neuroinflammation, and oxidative stress is highlighted, followed by recent evidence for their use as prognostic and diagnostic biomarkers for PD.

scholarly journals Sex- and age‐dependent alterations of splenic immune cell profile and NK cell phenotypes and function in C57BL/6J mice

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Kelly B. Menees ◽  
Rachael H. Earls ◽  
Jaegwon Chung ◽  
Janna Jernigan ◽  
Nikolay M. Filipov ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Sex Differences ◽  
Nk Cells ◽  
Immune Cell ◽  
Nk Cell ◽  
Spleen Weight ◽  
Age Related ◽  
And Function ◽  
Cell Phenotypes

Abstract Background Physiological homeostasis decline, immunosenescence, and increased risk for multiple diseases, including neurodegeneration, are all hallmarks of ageing. Importantly, it is known that the ageing process is sex-biased. For example, there are sex differences in predisposition for multiple age-related diseases, including neurodegenerative and autoimmune diseases. However, sex differences in age-associated immune phenotypes are not clearly understood. Results Here, we examined the effects of age on immune cell phenotypes in both sexes of C57BL/6J mice with a particular focus on NK cells. We found female-specific spleen weight increases with age and concordant reduction in the number of splenocytes per gram of spleen weight compared to young females. To evaluate sex- and age-associated changes in splenic immune cell composition, we performed flow cytometry analysis. In male mice, we observed an age-associated reduction in the frequencies of monocytes and NK cells; female mice displayed a reduction in B cells, NK cells, and CD8 + T cells and increased frequency of monocytes and neutrophils with age. We then performed a whole blood stimulation assay and multiplex analyses of plasma cytokines and observed age- and sex-specific differences in immune cell reactivity and basal circulating cytokine concentrations. As we have previously illustrated a potential role of NK cells in Parkinson’s disease, an age-related neurodegenerative disease, we further analyzed age-associated changes in NK cell phenotypes and function. There were distinct differences between the sexes in age-associated changes in the expression of NK cell receptors, IFN-γ production, and impairment of α-synuclein endocytosis. Conclusions This study demonstrates sex- and age-specific alterations in splenic lymphocyte composition, circulating cytokine/chemokine profiles, and NK cell phenotype and effector functions. Our data provide evidence that age-related physiological perturbations differ between the sexes which may help elucidate sex differences in age-related diseases, including neurodegenerative diseases, particularly Parkinson’s disease, where immune dysfunction is implicated in their etiology.

scholarly journals Age-related pathological impairments in induced neurons derived from patients with idiopathic Parkinson’s disease

2021 ◽  
Author(s):  
Janelle Drouin-Ouellet ◽  
Karolina Pircs ◽  
Emilie M. Legault ◽  
Marcella Birtele ◽  
Fredrik Nilsson ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Alpha Synuclein ◽  
Specific Model ◽  
Dermal Fibroblasts ◽  
Patient Specific ◽  
Idiopathic Parkinson’S Disease ◽  
Age Related ◽  
Idiopathic Parkinson's Disease ◽  
Induced Neurons

AbstractUnderstanding the pathophysiology of Parkinson’s disease has been hampered by the lack of models that recapitulate all the critical factors underlying its development. Here, we generated functional induced dopaminergic neurons (iDANs) that were directly reprogrammed from adult human dermal fibroblasts of patients with idiopathic Parkinson’s disease to investigate diseaserelevant pathology. We show that iDANs derived from Parkinson’s disease patients exhibit lower basal chaperone-mediated autophagy as compared to iDANs of healthy donors. Furthermore, stress-induced autophagy resulted in an accumulation of macroautophagic structures in induced neurons (iNs) derived from Parkinson’s disease patients, independently of the specific neuronal subtype but dependent on the age of the donor. Finally, we found that these impairments in patient-derived iNs lead to an accumulation of phosphorylated alpha-synuclein, a hallmark of Parkinson’s disease pathology. Taken together, our results demonstrate that direct neural reprogramming provides a patient-specific model to study aged neuronal features relevant to idiopathic Parkinson’s disease.

scholarly journals Alpha-synuclein alters the faecal viromes of rats in a gut-initiated model of Parkinson’s disease

2021 ◽  
Author(s):  
S. R. Stockdale ◽  
L. A. Draper ◽  
S. M. O’Donovan ◽  
W. Barton ◽  
O. O’Sullivan ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Nervous System ◽  
Lewy Body ◽  
Neurological Disorder ◽  
Alpha Synuclein ◽  
Observational Period ◽  
Β Diversity ◽  
Potential Trigger ◽  
The Brain

AbstractParkinson’s disease (PD) is a chronic neurological disorder associated with the misfolding of alpha-synuclein (α-syn) into Lewy body aggregates within nerve cells that contribute to their neurodegeneration. Recent evidence suggests α-syn aggregation may begin in the gut and travel to the brain along the vagus nerve, with microbes a potential trigger initiating the misfolding of α-syn. However, changes in the gut virome in response to α-syn alterations have not been investigated. In this study, we show longitudinal changes in the faecal virome of rats administered either monomeric or preformed fibrils (PFF) of α-syn directly into their enteric nervous system. Differential changes in rat viromes were observed when comparing monomeric and PFF α-syn. The virome β-diversity changes after α-syn treatment were compounded by the addition of LPS as an adjunct. Changes in the diversity of rat faecal viromes were observed after one month and did not resolve within the study’s five month observational period. Overall, these results suggest that microbiome alterations associated with PD may, partially, be reactive to host α-syn associated changes.

scholarly journals Non-Coding RNAs in the Brain-Heart Axis: The Case of Parkinson’s Disease

2020 ◽  
Vol 21 (18) ◽  
pp. 6513 ◽  
Author(s):  
Shubhra Acharya ◽  
Antonio Salgado-Somoza ◽  
Francesca Maria Stefanizzi ◽  
Andrew I. Lumley ◽  
Lu Zhang ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
High Throughput ◽  
Regulatory Networks ◽  
Current Knowledge ◽  
Circular Rnas ◽  
Clinical Markers ◽  
Wide Range ◽  
Non Coding Rnas ◽  
The Brain

Parkinson’s disease (PD) is a complex and heterogeneous disorder involving multiple genetic and environmental influences. Although a wide range of PD risk factors and clinical markers for the symptomatic motor stage of the disease have been identified, there are still no reliable biomarkers available for the early pre-motor phase of PD and for predicting disease progression. High-throughput RNA-based biomarker profiling and modeling may provide a means to exploit the joint information content from a multitude of markers to derive diagnostic and prognostic signatures. In the field of PD biomarker research, currently, no clinically validated RNA-based biomarker models are available, but previous studies reported several significantly disease-associated changes in RNA abundances and activities in multiple human tissues and body fluids. Here, we review the current knowledge of the regulation and function of non-coding RNAs in PD, focusing on microRNAs, long non-coding RNAs, and circular RNAs. Since there is growing evidence for functional interactions between the heart and the brain, we discuss the benefits of studying the role of non-coding RNAs in organ interactions when deciphering the complex regulatory networks involved in PD progression. We finally review important concepts of harmonization and curation of high throughput datasets, and we discuss the potential of systems biomedicine to derive and evaluate RNA biomarker signatures from high-throughput expression data.

Brain Grafting as a Treatment for Parkinson's Disease

Neurosurgery ◽  
1987 ◽  
Vol 20 (2) ◽  
pp. 335-342 ◽  
Author(s):  
Mark J. Perlow
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Clinical Manifestations ◽  
Dopamine Neurons ◽  
Clinical Aspects ◽  
Pathological Changes ◽  
Pharmacological Treatments ◽  
The Central Nervous System ◽  
The Brain

Abstract Parkinson's disease is an illness with neuropathological and neuroanatomical abnormalities in many areas of the central nervous system. Some clinical manifestations of this illness are correlated with pathological changes in the substantia nigra and with a loss of dopamine in the nigra and striatum. The most effective pharmacological treatments have used agents that either replace the lost dopamine or act as agonists on dopamine receptors. Recent studies in animal models of Parkinson's disease demonstrate that the loss of dopamine and many clinical manifestations of dopamine reduction can be reversed by transplantation of fetal dopamine-containing cells to specific dopamine-depleted areas of the brain. Long term viability of these transplants has also been demonstrated. The author suggests that the transplantation of dopamine neurons, even across species barriers, is a reasonable consideration for the treatment of human Parkinson's disease. This article reviews in detail the results of recent experiments and how the experience in these models might be utilized in determining a transplantation strategy for the treatment of specific clinical aspects of this illness.

scholarly journals The Contribution ofα-Synuclein Spreading to Parkinson’s Disease Synaptopathy

2017 ◽  
Vol 2017 ◽  
pp. 1-15 ◽  
Author(s):  
Francesca Longhena ◽  
Gaia Faustini ◽  
Cristina Missale ◽  
Marina Pizzi ◽  
PierFranco Spano ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Disorders ◽  
Physiological Conditions ◽  
Age Related ◽  
Endogenous Protein ◽  
Synaptic Failure ◽  
Nigrostriatal Neurons ◽  
Somatic Nervous System ◽  
The Brain

Synaptopathies are diseases with synapse defects as shared pathogenic features, encompassing neurodegenerative disorders such as Parkinson’s disease (PD). In sporadic PD, the most common age-related neurodegenerative movement disorder, nigrostriatal dopaminergic deficits are responsible for the onset of motor symptoms that have been related toα-synuclein deposition at synaptic sites. Indeed,α-synuclein accumulation can impair synaptic dopamine release and induces the death of nigrostriatal neurons. While in physiological conditions the protein can interact with and modulate synaptic vesicle proteins and membranes, numerous experimental evidences have confirmed that its pathological aggregation can compromise correct neuronal functioning. In addition, recent findings indicate thatα-synuclein pathology spreads into the brain and can affect the peripheral autonomic and somatic nervous system. Indeed, monomeric, oligomeric, and fibrillaryα-synuclein can move from cell to cell and can trigger the aggregation of the endogenous protein in recipient neurons. This novel “prion-like” behavior could further contribute to synaptic failure in PD and other synucleinopathies. This review describes the major findings supporting the occurrence ofα-synuclein pathology propagation in PD and discusses how this phenomenon could induce or contribute to synaptic injury and degeneration.

scholarly journals Blood Plasma of Patients with Parkinson’s Disease Increases Alpha-Synuclein Aggregation and Neurotoxicity

2016 ◽  
Vol 2016 ◽  
pp. 1-14 ◽  
Author(s):  
Peng Wang ◽  
Xin Li ◽  
Xuran Li ◽  
Weiwei Yang ◽  
Shun Yu
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Alternative Pathway ◽  
Lewy Bodies ◽  
Normal Subjects ◽  
Alpha Synuclein ◽  
Phosphatase 2A ◽  
Alpha Synuclein Aggregation ◽  
The Brain ◽  
Neighboring Neuron

A pathological hallmark of Parkinson’s disease (PD) is formation of Lewy bodies in neurons of the brain. This has been attributed to the spread of α-synuclein (α-syn) aggregates, which involves release of α-syn from a neuron and its reuptake by a neighboring neuron. We found that treatment with plasma from PD patients induced more α-syn phosphorylation and oligomerization than plasma from normal subjects (NS). Compared with NS plasma, PD plasma added to primary neuron cultures caused more cell death in the presence of extracellular α-syn. This was supported by the observations that phosphorylated α-syn oligomers entered neurons, rapidly increased accumulated thioflavin S-positive inclusions, and induced a series of metabolic changes that included activation of polo-like kinase 2, inhibition of glucocerebrosidase and protein phosphatase 2A, and reduction of ceramide levels, all of which have been shown to promote α-syn phosphorylation and aggregation. We also analyzed neurotoxicity of α-syn oligomers relative to plasma from different patients. Neurotoxicity was not related to age or gender of the patients. However, neurotoxicity was positively correlated with H&Y staging score. The modification in the plasma may promote spreading of α-syn aggregates via an alternative pathway and accelerate progression of PD.

scholarly journals Large-Scale Profiling of RBP-circRNA Interactions from Public CLIP-Seq Datasets

2019 ◽  
Author(s):  
Minzhe Zhang ◽  
Tao Wang ◽  
Guanghua Xiao ◽  
Yang Xie
Keyword(s):  
Large Scale ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Read Length ◽  
Circular Rnas ◽  
Binding Partners ◽  
Genome Wide ◽  
Wide Scale ◽  
And Function ◽  
Short Read Length

Circular RNAs are a special type of RNAs which recently attracted a lot of research interest in studying its formation and function. RNA binding proteins (RBPs) that bind circRNAs are important in these processes but are relatively less studied. CLIP-Seq technology has been invented and applied to profile RBP-RNA interactions on the genome-wide scale. While mRNAs are usually the focus of CLIP-Seq experiments, RBP-circRNA interactions could also be identified through specialized analysis of CLIP-Seq datasets. However, many technical difficulties are involved in this process, such as the usually short read length of CLIP-Seq reads. In this study, we created a pipeline called Clirc specialized for profiling circRNAs in CLIP-Seq data and analyzing the characteristics of RBP- circRNAs interactions. In conclusion, this is one of the first few studies to investigate circRNAs and their binding partners through repurposing CLIP-Seq datasets to our knowledge, and we hope our work will become a valuable resource for future studies into the biogenesis and function of circRNAs. Clirc software is available at https://github.com/Minzhe/Clirc

scholarly journals Dynamic changes in the CD163+ and CCR2+ peripheral monocytes during Parkinson’s disease

2021 ◽  
Author(s):  
Sara Konstantin Nissen ◽  
Kristine Farmen ◽  
Mikkel Carstensen ◽  
Claudia Schulte ◽  
David Goldeck ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Dendritic Cells ◽  
Alpha Synuclein ◽  
Mononuclear Phagocytes ◽  
Motor Symptoms ◽  
Hla Dr ◽  
Non Motor Symptoms ◽  
The Brain ◽  
Classical Monocytes

AbstractBackgroundAlpha-synuclein aggregates and accumulation are associated with immune activation and neurodegeneration in Parkinson’s disease. The immune activation is not only dependent on the brain-resident microglial cells but also involves peripheral immune cells, such as mononuclear phagocytes including monocytes and dendritic cells, found in the blood as well as infiltrated into the brain. Understanding the involvement of the peripheral immune component in Parkinson’s disease is essential for the development of immunomodulatory treatment, which might modify disease progression. We aimed to study the profile of circulating mononuclear phagocytes in early- and late-stage Parkinson’s disease by analyzing surface-expressed molecules related to phagocytosis, alpha-synuclein sensing, and tissue-migration.MethodsMulti-color flow cytometry on peripheral mononuclear cells from cross-sectional samples of 80 gender-balance individuals with early- and late-stage sporadic Parkinson’s disease, and 29 controls, as well as longitudinal samples from seven patients and one control. Cells were delineated into natural killer cells, monocyte subtypes, and dendritic cells with cell frequencies and surface marker expressions compared between patients and controls, and correlated with standardized clinical motor and non-motor scores.ResultsOverall, we found elevated frequencies and surface levels of markers related to migration (CCR2, CD11b) and phagocytosis (CD163) particularly on the elevated classical and intermediate monocytes in patients with Parkinson’s disease for less than five years. This corresponded to a decrease of non-classical monocytes and dendritic cells. We observed an increased HLA-DR expression late in disease and sexual-dimorphism with TLR-4 expression decreased in women with PD but not in males. The disease-associated immune changes on TLR4, CCR2, and CD11b were correlated with non-motor symptoms such as olfaction or cognition. While many alterations were normalized at late disease stage, other changes remained, such as the increased HLA-DR and CD163 expressions.ConclusionsOur data highlight a role for peripheral CD163+ and migration-competent classical monocytes in Parkinson’s disease. The study further suggests that the peripheral immune system is dynamically altered in Parkinson’s disease stages and directly related to both non-motor symptoms and the sex-bias of the disease.

scholarly journals RNA Dynamics in Alzheimer’s Disease

Molecules ◽  
2021 ◽  
Vol 26 (17) ◽  
pp. 5113
Author(s):  
Agnieszka Rybak-Wolf ◽  
Mireya Plass
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Mechanisms ◽  
Rna Binding ◽  
Neurodegenerative Disorder ◽  
Rna Binding Proteins ◽  
Current Evidence ◽  
Circular Rnas ◽  
Rna Dynamics ◽  
Age Related

Alzheimer’s disease (AD) is the most common age-related neurodegenerative disorder that heavily burdens healthcare systems worldwide. There is a significant requirement to understand the still unknown molecular mechanisms underlying AD. Current evidence shows that two of the major features of AD are transcriptome dysregulation and altered function of RNA binding proteins (RBPs), both of which lead to changes in the expression of different RNA species, including microRNAs (miRNAs), circular RNAs (circRNAs), long non-coding RNAs (lncRNAs), and messenger RNAs (mRNAs). In this review, we will conduct a comprehensive overview of how RNA dynamics are altered in AD and how this leads to the differential expression of both short and long RNA species. We will describe how RBP expression and function are altered in AD and how this impacts the expression of different RNA species. Furthermore, we will also show how changes in the abundance of specific RNA species are linked to the pathology of AD.

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