“Changes in soluble CD163 indicate monocyte involvement in cognitive deficits in Parkinson’s disease”

ABSTRACTParkinson’s disease is a neurodegenerative disorder with a significant immune component. Numerous studies have reported alterations on immune biomarkers in CSF and serum that associate with symptoms in PD patients. However, it is unclear, which specific immune cells are responsible for the changes in those biomarkers; since most of these cytokines or chemokines, can be produced by a variety of immune cells, or even neurons or glia cells in the brain. Here, we investigate a monocyte/macrophage-specific biomarker: sCD163, the soluble form of the receptor CD163. Our data from tow cohorts show that the CSF-sCD163 increases as the disease progresses, together with a correlated increase in PD-specific as well as neurodegeneration-associated disease biomarkers: alpha-synuclein, tau, and phosphorylated-Tau. Moreover, CSF-sCD163 levels were inversely correlated to the cognitive scores MMSE and MOCA, with higher sCD163 indicating lower cognitive capacity. sCD163 was also increased in serum, although only in female PD patients, suggesting a gender distinctive monocyte-related immune response. CSF-sCD163 also correlated with molecules associated with endothelial cells, tissue infiltration, and activation of B cells and T cells in the PD patients. This suggests activation of both the adaptive and the innate immune system along with recruitment of lymphocytes and monocytes to sites of inflammation in the brain. In serum, sCD163 was associated with pro-inflammatory cytokines and acute phase proteins, suggesting a relation to chronic systemic inflammation. Interestingly, our in vitro study suggests that sCD 163 might enhance alpha-synuclein uptake by myeloid cells without direct binding, thus participating in the clearance of alpha-synuclein. Accordingly, our data supports sCD163 as a potential cognition-related biomarker in PD and corroborates a role for monocytes both in peripheral and brain immune responses that could have direct consequences in the handling of alpha-synuclein.

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Alpha-Synuclein Induced Immune Cells Activation and Associated Therapy in Parkinson’s Disease

Frontiers in Aging Neuroscience ◽

10.3389/fnagi.2021.769506 ◽

2021 ◽

Vol 13 ◽

Author(s):

Ruichen Su ◽

Tian Zhou

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Immune System ◽

Immune Cells ◽

Neurodegenerative Disorder ◽

Alpha Synuclein ◽

Autoimmune Response ◽

T Helper ◽

Helper Type

Parkinson’s disease (PD) is a neurodegenerative disorder closely related to immunity. An important aspect of the pathogenesis of PD is the interaction between α-synuclein and a series of immune cells. Studies have shown that accumulation of α-synuclein can induce an autoimmune response that accelerates the progression of PD. This study discusses the mechanisms underlying the interaction between α-synuclein and the immune system. During the development of PD, abnormally accumulated α-synuclein becomes an autoimmune antigen that binds to Toll-like receptors (TLRs) that activate microglia, which differentiate into the microglia type 1 (M1) subtype. The microglia activate intracellular inflammatory pathways, induce the release of proinflammatory cytokines, and promote the differentiation of cluster of differentiation 4 + (CD4 +) T cells into proinflammatory T helper type 1 (Th1) and T helper type 17 (Th17) subtypes. Given the important role of α-synuclein in the immune system of the patients with PD, identifying potential targets of immunotherapy related to α-synuclein is critical for slowing disease progression. An enhanced understanding of immune-associated mechanisms in PD can guide the development of associated therapeutic strategies in the future.

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

10.1101/2021.03.29.437468 ◽

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.

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

npj Parkinson s Disease ◽

10.1038/s41531-021-00265-9 ◽

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.

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Parkinson's Disease

Advances in Medical Diagnosis, Treatment, and Care - Handbook of Research on Critical Examinations of Neurodegenerative Disorders ◽

10.4018/978-1-5225-5282-6.ch012 ◽

2019 ◽

pp. 252-273 ◽

Cited By ~ 1

Author(s):

Vaibhav Walia ◽

Ashish Gakkhar ◽

Munish Garg

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Substantia Nigra ◽

Dopaminergic Neurons ◽

Older Patients ◽

Neurodegenerative Disorder ◽

Progressive Loss ◽

The Brain

Parkinson's disease (PD) is a neurodegenerative disorder in which a progressive loss of the dopaminergic neurons occurs. The loss of the neurons is most prominent in the substantia nigra region of the brain. The prevalence of PD is much greater among the older patients suggesting the risk of PD increases with the increase of age. The exact cause of the neurodegeneration in PD is not known. In this chapter, the authors introduce PD, demonstrate its history, pathogenesis, neurobiology, sign and symptoms, diagnosis, and pharmacotherapy.

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Molecular evolutionary and structural analysis of human UCHL1 gene demonstrates the relevant role of intragenic epistasis in Parkinson’s disease and other neurological disorders

BMC Evolutionary Biology ◽

10.1186/s12862-020-01684-7 ◽

2020 ◽

Vol 20 (1) ◽

Author(s):

Muhammad Saqib Nawaz ◽

Razia Asghar ◽

Nashaiman Pervaiz ◽

Shahid Ali ◽

Irfan Hussain ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Structural Analysis ◽

Neurodegenerative Disorder ◽

Soluble Form ◽

Evolutionary Pattern ◽

Protein Segment ◽

Interaction Sites ◽

Relevant Role

Abstract Background Parkinson’s disease (PD) is the second most common neurodegenerative disorder. PD associated human UCHL1 (Ubiquitin C-terminal hydrolase L1) gene belongs to the family of deubiquitinases and is known to be highly expressed in neurons (1–2% in soluble form). Several functions of UCHL1 have been proposed including ubiquitin hydrolyze activity, ubiquitin ligase activity and stabilization of the mono-ubiquitin. Mutations in human UCHL1 gene have been associated with PD and other neurodegenerative disorders. The present study aims to decipher the sequence evolutionary pattern and structural dynamics of UCHL1. Furthermore, structural and interactional analysis of UCHL1 was performed to help elucidate the pathogenesis of PD. Results The phylogenetic tree topology suggests that the UCHL1 gene had originated in early gnathostome evolutionary history. Evolutionary rate analysis of orthologous sequences reveals strong purifying selection on UCHL1. Comparative structural analysis of UCHL1 pinpoints an important protein segment spanning amino acid residues 32 to 39 within secretion site with crucial implications in evolution and PD pathogenesis through a well known phenomenon called intragenic epistasis. Identified critical protein segment appears to play an indispensable role in protein stability, proper protein conformation as well as harboring critical interaction sites. Conclusions Conclusively, the critical protein segment of UCHL1 identified in the present study not only demonstrates the relevant role of intraprotein conformational epistasis in the pathophysiology of PD but also offers a novel therapeutic target for the disease.

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What Is the Evidence that Parkinson’s Disease Is a Prion Disorder, Which Originates in the Gut?

International Journal of Molecular Sciences ◽

10.3390/ijms19113573 ◽

2018 ◽

Vol 19 (11) ◽

pp. 3573 ◽

Cited By ~ 12

Author(s):

Małgorzata Kujawska ◽

Jadwiga Jodynis-Liebert

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Nervous System ◽

Neurodegenerative Disorder ◽

Human Subjects ◽

Gastrointestinal Symptoms ◽

Convincing Evidence ◽

Substantia Nigra Pars Compacta ◽

Motor Nucleus ◽

The Brain

Parkinson’s disease (PD) is a neurodegenerative disorder resulting from degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc). PD is characterized by motor dysfunctions as well as gastrointestinal symptoms and mental impairment. The pathological hallmark of PD is an accumulation of misfolded α-synuclein aggregates within the brain. The etiology of PD and related synucleinopathy is poorly understood, but recently, the hypothesis that α-synuclein pathology spreads in a prion-like fashion originating in the gut has gained much scientific attention. A crucial clue was the appearance of constipation before the onset of motor symptoms, gut dysbiosis and synucleinopathy in PD patients. Another line of evidence, demonstrating accumulation of α-synuclein within the peripheral autonomic nervous system (PANS), including the enteric nervous system (ENS), and the dorsal motor nucleus of the vagus (DMV) support the concept that α-synuclein can spread from the ENS to the brain by the vagus nerve. The decreased risk of PD following truncal vagotomy supports this. The convincing evidence of the prion-like behavior of α-synuclein came from postmortem observations that pathological α-synuclein inclusions appeared in healthy grafted neurons. In this review, we summarize the available data from human subjects’ research and animal experiments, which seem to be the most suggestive for explaining the hypotheses.

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

Parkinson s Disease ◽

10.1155/2016/7596482 ◽

2016 ◽

Vol 2016 ◽

pp. 1-14 ◽

Cited By ~ 2

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.

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α-Synuclein pre-formed fibrils induce prion-like protein aggregation and neurotoxicity in C. elegans models of Parkinson's disease

10.1101/2021.11.11.468276 ◽

2021 ◽

Author(s):

Merry Chen ◽

Julie Vincent ◽

Alexis Ezeanii ◽

Saurabh Wakade ◽

Shobha Yerigenahally ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Neurodegenerative Disorder ◽

Motor Deficit ◽

Rodent Models ◽

Neuron Degeneration ◽

C Elegans ◽

Dopaminergic Neurodegeneration ◽

Disease Mechanisms ◽

The Brain

Parkinson's disease (PD) is a debilitating neurodegenerative disorder characterized by progressive motor decline and the aggregation of α-synuclein protein. Growing evidence suggests that α-synuclein aggregates may spread from neurons of the digestive tract to the brain in a prion-like manner. While rodent models have recapitulated gut-to-brain α-synuclein transmission, animal models that are amenable to high-throughput investigations are needed to facilitate the discovery of disease mechanisms. Here we describe the first C. elegans models in which feeding with α-synuclein pre-formed fibrils (PFFs) induced prion-like dopamine neuron degeneration and seeding of aggregation of human α-synuclein expressed in the host. PFF acceleration of α-synuclein aggregation in C. elegans muscle cells was associated with a progressive motor deficit, whereas feeding with α-synuclein monomer produced much milder effects. RNAi-mediated knockdown of the C. elegans syndecan sdn-1, and enzymes involved in heparan sulfate proteoglycan biosynthesis, afforded protection from PFF-induced seeding of aggregation and toxicity, as well as dopaminergic neurodegeneration. This work offers new models by which to investigate gut-derived α-synuclein spreading and propagation of disease.

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

10.1101/2021.03.15.21253572 ◽

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.

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Heterogeneity of Incipient Atrophy Patterns in Parkinson’s Disease

10.1101/466086 ◽

2018 ◽

Author(s):

Pedro D. Maia ◽

Sneha Pandya ◽

Justin Torok ◽

Ajay Gupta ◽

Yashar Zeighami ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Substantia Nigra ◽

Neurodegenerative Disorder ◽

Neuronal Loss ◽

High Variability ◽

Clinical Value ◽

Optimization Routine ◽

Penalized Optimization ◽

The Brain

AbstractParkinson’s Disease (PD) is a the second most common neurodegenerative disorder after Alzheimer’s disease and is characterized by cell death in the amygdala and in substructures of the basal ganglia such as the substantia nigra. Since neuronal loss in PD leads to measurable atrophy patterns in the brain, there is clinical value in understanding where exactly the pathology emerges in each patient and how incipient atrophy relates to the future spread of disease. A recent seed-inference algorithm combining an established network-diffusion model with an L1-penalized optimization routine led to new insights regarding the non-stereotypical origins of Alzheimer’s pathologies across individual subjects. Here, we leverage the same technique to PD patients, demonstrating that the high variability in their atrophy patterns also translates into heterogeneous seed locations. Our individualized seeds are significantly more predictive of future atrophy than a single seed placed at the substantia nigra or the amygdala. We also found a clear distinction in seeding patterns between two PD subgroups – one characterized by predominant involvement of brainstem and ventral nuclei, and the other by more widespread frontal and striatal cortices. This might be indicative of two distinct etiological mechanisms operative in PD. Ultimately, our methods demonstrate that the early stages of the disease may exhibit incipient atrophy patterns that are more complex and variable than generally appreciated.

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