Beta-Amyloid, Phospho-Tau and Alpha-Synuclein Deposits Similar to Those in the Brain Are Not Identified in the Eyes of Alzheimer's and Parkinson's Disease Patients

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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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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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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Association Between Decreased Srpk3 Expression And An Increase In Substantia Nigra Alpha-Synuclein Levels In An MPTP-Induced Parkinson’s Disease Mouse Model

10.21203/rs.3.rs-1207279/v1 ◽

2022 ◽

Author(s):

Min Hyung Seo ◽

Sujung Yeo

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Substantia Nigra ◽

Dopaminergic Neurons ◽

Cell Loss ◽

Alpha Synuclein ◽

Mice Model ◽

Dopaminergic Cell ◽

The Brain

Abstract Parkinson’s disease (PD) is known as the second most common neurodegenerative disease, which is caused by destruction of dopaminergic neurons in the substantia nigra (SN) of the brain; however, the reason for the death of dopaminergic neurons remains unclear. An increase in α-synuclein (α-syn) is considered an important factor in the pathogenesis of PD. In the current study, we investigated the association between PD and serine/arginine-rich protein specific kinase 3 (Srpk3) in MPTP-induced parkinsonism mice model and in SH-SY5Y cells treated with MPP+. Srpk3 expression was significantly downregulated, while tyrosine hydroxylase (TH) decreased and α-synuclein (α-syn) increased after 4 weeks of MPTP intoxication treatment. Dopaminergic cell reduction and α-syn increase were demonstrated by inhibiting Srpk3 expression by siRNA in SH-SY5Y cells. Moreover, a decrease in Srpk3 expression upon siRNA treatment promoted dopaminergic cell reduction and α-syn increase in SH-SY5Y cells treated with MPP+. These results suggest that the decrease in Srpk3 expression due to Srpk3 siRNA caused both a decrease in TH and an increase in α-syn. This raises new possibilities for studying how Srpk3 controls dopaminergic cells and α-syn expression, which may be related to the pathogenesis of PD. Our results provide an avenue for understanding the role of Srpk3 during dopaminergic cell loss and α-syn increase in the SN. Furthermore, this study could support a therapeutic possibility for PD in that the maintenance of Srpk3 expression inhibited dopaminergic cell reduction.

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The Two Faces of Exosomes in Parkinson’s Disease: From Pathology to Therapy

The Neuroscientist ◽

10.1177/1073858421990001 ◽

2021 ◽

pp. 107385842199000

Author(s):

Maria Izco ◽

Estefania Carlos ◽

Lydia Alvarez-Erviti

Keyword(s):

Parkinson’S Disease ◽

Drug Delivery ◽

Parkinson's Disease ◽

Drug Delivery System ◽

Glial Cells ◽

Delivery System ◽

Alpha Synuclein ◽

Macromolecular Drugs ◽

The Brain

Accumulating evidence suggests that exosomes play a key role in Parkinson’s disease (PD). Exosomes may contribute to the PD progression facilitating the spread of pathological alpha-synuclein or activating immune cells. Glial cells also release exosomes, and transmission of exosomes derived from activated glial cells containing inflammatory mediators may contribute to the propagation of the neuroinflammatory response. Glia-to-neuron transmission of exosomes containing alpha-synuclein may contribute to alpha-synuclein propagation and neurodegeneration. Additionally, miRNAs can be transmitted among cells via exosomes inducing changes in the genetic program of the target cell contributing to PD progression. Exosomes also represent a promising drug delivery system. The brain is a difficult target for drugs of all classes because the blood-brain barrier excludes most macromolecular drugs. One of the major challenges is the development of vehicles for robust delivery to the brain. Targeted exosomes may have the potential for delivering therapeutic agents, including proteins and gene therapy molecules, into the brain. This review summarizes recent advances in the role of exosomes in PD pathology progression and their potential use as drug delivery system for PD treatment, the two faces of the exosomes in PD.

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The Gut–Brain Axis and Its Relation to Parkinson’s Disease: A Review

Frontiers in Aging Neuroscience ◽

10.3389/fnagi.2021.782082 ◽

2022 ◽

Vol 13 ◽

Author(s):

Emily M. Klann ◽

Upuli Dissanayake ◽

Anjela Gurrala ◽

Matthew Farrer ◽

Aparna Wagle Shukla ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Current Knowledge ◽

Lewy Bodies ◽

Disease Diagnosis ◽

Alpha Synuclein ◽

Motor Symptoms ◽

Abnormal Gait ◽

Non Motor Symptoms ◽

The Brain

Parkinson’s disease is a chronic neurodegenerative disease characterized by the accumulation of misfolded alpha-synuclein protein (Lewy bodies) in dopaminergic neurons of the substantia nigra and other related circuitry, which contribute to the development of both motor (bradykinesia, tremors, stiffness, abnormal gait) and non-motor symptoms (gastrointestinal issues, urinogenital complications, olfaction dysfunction, cognitive impairment). Despite tremendous progress in the field, the exact pathways and mechanisms responsible for the initiation and progression of this disease remain unclear. However, recent research suggests a potential relationship between the commensal gut bacteria and the brain capable of influencing neurodevelopment, brain function and health. This bidirectional communication is often referred to as the microbiome–gut–brain axis. Accumulating evidence suggests that the onset of non-motor symptoms, such as gastrointestinal manifestations, often precede the onset of motor symptoms and disease diagnosis, lending support to the potential role that the microbiome–gut–brain axis might play in the underlying pathological mechanisms of Parkinson’s disease. This review will provide an overview of and critically discuss the current knowledge of the relationship between the gut microbiota and Parkinson’s disease. We will discuss the role of α-synuclein in non-motor disease pathology, proposed pathways constituting the connection between the gut microbiome and the brain, existing evidence related to pre- and probiotic interventions. Finally, we will highlight the potential opportunity for the development of novel preventative measures and therapeutic options that could target the microbiome–gut–brain axis in the context of Parkinson’s disease.

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Accumulation of alpha-synuclein within the liver, potential role in the clearance of brain pathology associated with Parkinson’s disease

Acta Neuropathologica Communications ◽

10.1186/s40478-021-01136-3 ◽

2021 ◽

Vol 9 (1) ◽

Author(s):

Juan F. Reyes ◽

Sara Ekmark-Léwen ◽

Marina Perdiki ◽

Therése Klingstedt ◽

Alana Hoffmann ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Potential Role ◽

Alpha Synuclein ◽

Wild Type ◽

Junction Protein ◽

The Central Nervous System ◽

Gap Junction Protein ◽

First Time ◽

The Brain

AbstractAlpha-synuclein (α-syn) aggregation is the hallmark pathological lesion in brains of patients with Parkinson’s disease (PD) and related neurological disorders characterized as synucleinopathies. Accumulating evidence now indicates that α-syn deposition is also present within the gut and other peripheral organs outside the central nervous system (CNS). In the current study, we demonstrate for the first time that α-syn pathology also accumulates within the liver, the main organ responsible for substance clearance and detoxification. We further demonstrate that cultured human hepatocytes readily internalize oligomeric α-syn assemblies mediated, at least in part, by the gap junction protein connexin-32 (Cx32). Moreover, we identified a time-dependent accumulation of α-syn within the liver of three different transgenic (tg) mouse models expressing human α-syn under CNS-specific promoters, despite the lack of α-syn mRNA expression within the liver. Such a brain-to-liver transmission route could be further corroborated by detection of α-syn pathology within the liver of wild type mice one month after a single striatal α-syn injection. In contrast to the synucleinopathy models, aged mice modeling AD rarely show any amyloid-beta (Aß) deposition within the liver. In human post-mortem liver tissue, we identified cases with neuropathologically confirmed α-syn pathology containing α-syn within hepatocellular structures to a higher degree (75%) than control subjects without α-syn accumulation in the brain (57%). Our results reveal that α-syn accumulates within the liver and may be derived from the brain or other peripheral sources. Collectively, our findings indicate that the liver may play a role in the clearance and detoxification of pathological proteins in PD and related synucleinopathies.

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1148 Conceiving A Connected, Preventative Treatment Stance Across The Brain-gut-microbiota Axis In Prodromal Parkinson’s Disease: The Power Of Preventative Sleep Health

SLEEP ◽

10.1093/sleep/zsaa056.1142 ◽

2020 ◽

Vol 43 (Supplement_1) ◽

pp. A437-A438

Author(s):

J F Chandler ◽

M M Bullock ◽

N G Chandler ◽

S M Nelson ◽

S P Hoyle ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Literature Review ◽

Gut Microbiota ◽

Systematic Literature Review ◽

Alpha Synuclein ◽

Current Treatment ◽

Reciprocal Relationship ◽

Treatment Research ◽

The Brain

Abstract Introduction Early non-motor symptoms of Parkinson’s Disease (PD) include sleep and digestive disturbances that share a common pathology via alpha-synuclein (AS) deposition in the central nervous system (CNS) and formation in the enteric (ENS). The concept of prodromal PD as expressed by the brain-gut-microbiota axis continues to gain credibility across multiple literatures; yet, no unified treatment plan has been suggested. Disconnected, symptomatic treatment of prodromal PD may unintentionally hasten its development via compromise of REM sleep quality and reciprocal gut health. A more connected, comprehensive approach is needed. We conducted a systematic literature review to hypothesize next steps in treatment research for prodromal PD. Methods A systematic literature review using the Boolean combinations of “ALPHA-SYNUCLEIN” & - “SLEEP”, “GUT MICROBIOME”, and “EXERCISE” in all fields, restricted to the last 5 years, focusing on specification of prodromal PD, was conducted. Results were combined with an examination of current treatment practices in PD. Results 38 articles met inclusion criteria. Results were categorized through a presupposed primacy of sleep. Conclusion Due to the emerging nature of the prodromal PD idea, current treatment practice is myopic and may contribute to the progression of PD. Specifically, 1) sedative-hypnotic sleep interventions suppress REM, where clearing of CNS alpha-synuclein occurs, and 2) proton-pump inhibitors (PPI) cause significant gut dysbiosis, which may contribute to initial AS misfolding in the gut. Early identification of prodromal PD symptoms via cross-referenced clinical interview may allow for early behavioral interventions that underlie healthy brain-gut-microbiota axis functioning. Results outline specific measures that may slow PD-related synucleinopothies. The highest impact practices in this regard are REM-focused sleep hygiene and cardiovascular conditioning in a reciprocal relationship, highlighting the necessity of an early-intervention, preventative health model for conquering PD. Support This work was made possible in part by a donation from Drs. Shane Pitts and Michelle Hilgeman in support of Birmingham-Southern College’s Southern Sleep Laboratory.

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Synthesis of Alginate-Curcumin Nanocomposite and Its Protective Role in Transgenic Drosophila Model of Parkinson’s Disease

ISRN Pharmacology ◽

10.1155/2013/794582 ◽

2013 ◽

Vol 2013 ◽

pp. 1-8 ◽

Cited By ~ 23

Author(s):

Yasir Hasan Siddique ◽

Wasi Khan ◽

Braj Raj Singh ◽

Alim H. Naqvi

Keyword(s):

Oxidative Stress ◽

Parkinson’S Disease ◽

Parkinson's Disease ◽

Lewy Bodies ◽

Protective Role ◽

Alpha Synuclein ◽

Lower Permeability ◽

Normal Human ◽

Climbing Ability ◽

The Brain

The genetic models in Drosophila provide a platform to understand the mechanism associated with degenerative diseases. The model for Parkinson's disease (PD) based on normal human alpha-synuclein (αS) expression was used in the present study. The aggregation of αS in brain leads to the formation of Lewy bodies and selective loss of dopaminergic neurons due to oxidative stress. Polyphenols generally have the reduced oral bioavailability, increased metabolic turnover, and lower permeability through the blood brain barrier. In the present study, the effect of synthesized alginate-curcumin nanocomposite was studied on the climbing ability of the PD model flies, lipid peroxidation, and apoptosis in the brain of PD model flies. The alginate-curcumin nanocomposite at final doses of 10−5, 10−3, and 10−1 g/mL was supplemented with diet, and the flies were allowed to feed for 24 days. A significant dose-dependent delay in the loss of climbing ability and reduction in the oxidative stress and apoptosis in the brain of PD model flies were observed. The results suggest that alginate-curcumin nanocomposite is potent in delaying the climbing disability of PD model flies and also reduced the oxidative stress as well as apoptosis in the brain of PD model flies.

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