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Review
. 2020 Jul 14;9(7):1687.
doi: 10.3390/cells9071687.

Inflammation in Parkinson's Disease: Mechanisms and Therapeutic Implications

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Review

Inflammation in Parkinson's Disease: Mechanisms and Therapeutic Implications

Marta Pajares et al. Cells. .
Free PMC article

Abstract

Parkinson's disease (PD) is a common neurodegenerative disorder primarily characterized by the death of dopaminergic neurons that project from the substantia nigra pars compacta. Although the molecular bases for PD development are still little defined, extensive evidence from human samples and animal models support the involvement of inflammation in onset or progression. However, the exact trigger for this response remains unclear. Here, we provide a systematic review of the cellular mediators, i.e., microglia, astroglia and endothelial cells. We also discuss the genetic and transcriptional control of inflammation in PD and the immunomodulatory role of dopamine and reactive oxygen species. Finally, we summarize the preclinical and clinical approaches targeting neuroinflammation in PD.

Keywords: Parkinson’s disease; immune system; neurodegeneration; neuroinflammation; therapy.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Review
. 2020 Nov 10;21(22):8421.
doi: 10.3390/ijms21228421.

Neurodegeneration and Inflammation-An Interesting Interplay in Parkinson's Disease

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Review

Neurodegeneration and Inflammation-An Interesting Interplay in Parkinson's Disease

Chrysoula Marogianni et al. Int J Mol Sci. .
Free PMC article

Abstract

Parkinson's disease (PD) is a neurodegenerative disorder, caused by, so far, unknown pathogenetic mechanisms. There is no doubt that pro-inflammatory immune-mediated mechanisms are pivotal to the pathogenicity and progression of the disease. In this review, we highlight the binary role of microglia activation in the pathophysiology of the disorder, both neuroprotective and neuromodulatory. We present how the expression of several cytokines implicated in dopaminergic neurons (DA) degeneration could be used as biomarkers for PD. Viral infections have been studied and correlated to the disease progression, usually operating as trigger factors for the inflammatory process. The gut-brain axis and the possible contribution of the peripheral bowel inflammation to neuronal death, mainly dopaminergic neurons, seems to be a main contributor of brain neuroinflammation. The role of the immune system has also been analyzed implicating a-synuclein in the activation of innate and adaptive immunity. We also discuss therapeutic approaches concerning PD and neuroinflammation, which have been studied in experimental and in vitro models and data stemming from epidemiological studies.

Keywords: Parkinson’s; autoimmunity; neurodegeneration; neuroinflammation.

Conflict of interest statement

The authors declare no conflict of interest.

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Review
. 2018 Jun 6;19(6):1689.
doi: 10.3390/ijms19061689.

Microbiome-Gut-Brain Axis and Toll-Like Receptors in Parkinson's Disease

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Review

Microbiome-Gut-Brain Axis and Toll-Like Receptors in Parkinson's Disease

Valentina Caputi et al. Int J Mol Sci. .
Free PMC article

Abstract

Parkinson’s disease (PD) is a progressively debilitating neurodegenerative disease characterized by α-synucleinopathy, which involves all districts of the brain-gut axis, including the central, autonomic and enteric nervous systems. The highly bidirectional communication between the brain and the gut is markedly influenced by the microbiome through integrated immunological, neuroendocrine and neurological processes. The gut microbiota and its relevant metabolites interact with the host via a series of biochemical and functional inputs, thereby affecting host homeostasis and health. Indeed, a dysregulated microbiota-gut-brain axis in PD might lie at the basis of gastrointestinal dysfunctions which predominantly emerge many years prior to the diagnosis, corroborating the theory that the pathological process is spread from the gut to the brain. Toll-like receptors (TLRs) play a crucial role in innate immunity by recognizing conserved motifs primarily found in microorganisms and a dysregulation in their signaling may be implicated in α-synucleinopathy, such as PD. An overstimulation of the innate immune system due to gut dysbiosis and/or small intestinal bacterial overgrowth, together with higher intestinal barrier permeability, may provoke local and systemic inflammation as well as enteric neuroglial activation, ultimately triggering the development of alpha-synuclein pathology. In this review, we provide the current knowledge regarding the relationship between the microbiota-gut⁻brain axis and TLRs in PD. A better understanding of the dialogue sustained by the microbiota-gut-brain axis and innate immunity via TLR signaling should bring interesting insights in the pathophysiology of PD and provide novel dietary and/or therapeutic measures aimed at shaping the gut microbiota composition, improving the intestinal epithelial barrier function and balancing the innate immune response in PD patients, in order to influence the early phases of the following neurodegenerative cascade.

Keywords: Parkinson’s disease; brain-gut axis; central nervous system; enteric microbiota; enteric nervous system; gastrointestinal dysfunctions; glial cells; gut dysbiosis; innate immunity; intestinal barrier permeability; microglia; neurons; pharmacological treatment; probiotics; toll-like receptors; α-synuclein.

Conflict of interest statement

The authors declare no conflict of interest.

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Review
. 2020 Sep;267(9):2507-2523.
doi: 10.1007/s00415-019-09320-1. Epub 2019 Apr 30.

Parkinson's disease and the gastrointestinal microbiome

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Review

Parkinson's disease and the gastrointestinal microbiome

Michal Lubomski et al. J Neurol. 2020 Sep.

Abstract

Recently, there has been a surge in awareness of the gastrointestinal microbiome (GM) and its role in health and disease. Of particular note is an association between the GM and Parkinson's disease (PD) and the realisation that the GM can act via a complex bidirectional communication between the gut and the brain. Compelling evidence suggests that a shift in GM composition may play an important role in the pathogenesis of PD by facilitating the characteristic ascending neurodegenerative spread of α-synuclein aggregates from the enteric nervous system to the brain. Here, we review evidence linking GM changes with PD, highlighting mechanisms supportive of pathological α-synuclein spread and intestinal inflammation in PD. We summarise existing patterns and correlations seen in clinical studies of the GM in PD, together with the impacts of non-motor symptoms, medications, lifestyle, diet and ageing on the GM. Roles of GM modulating therapies including probiotics and faecal microbiota transplantation are discussed. Encouragingly, alterations in the GM have repeatedly been observed in PD, supporting a biological link and highlighting it as a potential therapeutic target.

Keywords: Biomarker; Gastrointestinal microbiome; Gastrointestinal microbiota; Gut dysbiosis; Medications; Parkinson’s disease.

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Review
. 2018 Aug;45:53-61.
doi: 10.1016/j.arr.2018.04.004. Epub 2018 Apr 26.

Dysbiosis of gut microbiota and microbial metabolites in Parkinson's Disease

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Review

Dysbiosis of gut microbiota and microbial metabolites in Parkinson's Disease

Meng-Fei Sun et al. Ageing Res Rev. 2018 Aug.

Abstract

Gut microbial dysbiosis and alteration of microbial metabolites in Parkinson's disease (PD) have been increasingly reported. Dysbiosis in the composition and abundance of gut microbiota can affect both the enteric nervous system and the central nervous system (CNS), indicating the existence of a microbiota-gut-brain axis and thereby causing CNS diseases. Disturbance of the microbiota-gut-brain axis has been linked to specific microbial products that are related to gut inflammation and neuroinflammation. Future directions should therefore focus on the exploration of specific gut microbes or microbial metabolites that contribute to the development of PD. Microbiota-targeted interventions, such as antibiotics, probiotics and fecal microbiota transplantation, have been shown to favorably affect host health. In this review, recent findings regarding alterations and the role of gut microbiota and microbial metabolites in PD are summarized, and potential molecular mechanisms and microbiota-targeted interventions in PD are discussed.

Keywords: Central nervous system; Gut microbiota; Microbial molecules; Microbiota-targeted therapies; Parkinson's disease; Short-chain fatty acids.

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Review
. 2018 Apr 16;2018:4784268.
doi: 10.1155/2018/4784268. eCollection 2018.

Linking Neuroinflammation and Neurodegeneration in Parkinson's Disease

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Review

Linking Neuroinflammation and Neurodegeneration in Parkinson's Disease

Géraldine Gelders et al. J Immunol Res. .
Free PMC article

Abstract

Neurodegenerative diseases such as Parkinson's disease (PD) and Alzheimer's disease (AD) impose a pressing burden on our developed and consequently aging society. Misfolded protein aggregates are a critical aspect of several neurodegenerative diseases. Nevertheless, several questions remain unanswered regarding the role of misfolded protein aggregates and the cause of neuronal cell death. Recently, it has been postulated that neuroinflammatory processes might play a crucial role in the pathogenesis of PD. Numerous postmortem, brain imaging, epidemiological, and animal studies have documented the involvement of the innate and adaptive immunity in neurodegeneration. Whether these inflammatory processes are directly involved in the etiology of PD or represent secondary consequences of nigrostriatal pathway injury is the subject of intensive research. Immune alterations in response to extracellular α-synuclein may play a critical role in modulating Parkinson's disease progression. In this review, we address the current concept of neuroinflammation and its involvement in PD-associated neurodegeneration.

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Review
. 2019;9(s2):S331-S344.
doi: 10.3233/JPD-191729.

Inflammatory Bowel Diseases and Parkinson's Disease

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Free PMC article
Review

Inflammatory Bowel Diseases and Parkinson's Disease

Tomasz Brudek. J Parkinsons Dis. 2019.
Free PMC article

Abstract

The etiology of Parkinson's disease (PD) is multifactorial, with genetics, aging, and environmental agents all a part of the PD pathogenesis. Widespread aggregation of the α-synuclein protein in the form of Lewy bodies and Lewy neurites, and degeneration of substantia nigra dopamine neurons are the pathological hallmarks of PD. Inflammatory responses manifested by glial reactions, T cell infiltration, and increased expression of inflammatory cytokines, as well as other toxic mediators derived from activated glial cells, are currently recognized as prominent features of PD. Experimental, clinical and epidemiological data suggest that intestinal inflammation contributes to the pathogenesis of PD, and the increasing number of studies suggests that the condition may start in the gastrointestinal system years before any motor symptoms develop. Patients with inflammatory bowel disease (IBD) have a higher risk of developing PD compared with non-IBD individuals. Gene association study has found a genetic link between IBD and PD, and an evidence from animal studies suggests that gut inflammation, similar to that observed in IBD, may induce loss of dopaminergic neurons. Based on preclinical models of PD, it is suggested that the enteric microbiome changes early in PD, and gut infections trigger α-synuclein release and aggregation. In this paper, the possible link between IBD and PD is reviewed based on the available literature. Given the potentially critical role of gastrointestinal pathology in PD pathogenesis, there is reason to suspect that IBD or its treatments may impact PD risk. Thus, clinicians should be aware of PD symptoms in IBD patients.

Keywords: Crohn’s disease; Parkinson’s disease; brain-gut axis; enteric nervous system; gastrointestinal track inflammation; inflammation; inflammatory bowel disease; ulcerative colitis.

Conflict of interest statement

The author has no conflict of interest to report.

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. 2016 Dec 1;167(6):1469-1480.e12.
doi: 10.1016/j.cell.2016.11.018.

Gut Microbiota Regulate Motor Deficits and Neuroinflammation in a Model of Parkinson's Disease

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Gut Microbiota Regulate Motor Deficits and Neuroinflammation in a Model of Parkinson's Disease

Timothy R Sampson et al. Cell. .
Free PMC article

Abstract

The intestinal microbiota influence neurodevelopment, modulate behavior, and contribute to neurological disorders. However, a functional link between gut bacteria and neurodegenerative diseases remains unexplored. Synucleinopathies are characterized by aggregation of the protein α-synuclein (αSyn), often resulting in motor dysfunction as exemplified by Parkinson's disease (PD). Using mice that overexpress αSyn, we report herein that gut microbiota are required for motor deficits, microglia activation, and αSyn pathology. Antibiotic treatment ameliorates, while microbial re-colonization promotes, pathophysiology in adult animals, suggesting that postnatal signaling between the gut and the brain modulates disease. Indeed, oral administration of specific microbial metabolites to germ-free mice promotes neuroinflammation and motor symptoms. Remarkably, colonization of αSyn-overexpressing mice with microbiota from PD-affected patients enhances physical impairments compared to microbiota transplants from healthy human donors. These findings reveal that gut bacteria regulate movement disorders in mice and suggest that alterations in the human microbiome represent a risk factor for PD.

Keywords: Parkinson’s disease; gut-brain axis; microbiome; microglia; mouse model; short chain fatty acids; synuclein.

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Review
. 2016 Oct;15(10):1005-11.
doi: 10.1016/j.autrev.2016.07.022. Epub 2016 Aug 4.

Parkinson's disease: Autoimmunity and neuroinflammation

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Review

Parkinson's disease: Autoimmunity and neuroinflammation

Armando De Virgilio et al. Autoimmun Rev. 2016 Oct.

Erratum in

Abstract

Parkinson's disease is a neurodegenerative disease that causes the death of dopaminergic neurons in the substantia nigra. The resulting dopamine deficiency in the basal ganglia leads to a movement disorder that is characterized by classical parkinsonian motor symptoms. Parkinson's disease is recognized as the most common neurodegenerative disorder after Alzheimer's disease. PD ethiopathogenesis remains to be elucidated and has been connected to genetic, environmental and immunologic conditions. The past decade has provided evidence for a significant role of the immune system in PD pathogenesis, either through inflammation or an autoimmune response. Several autoantibodies directed at antigens associated with PD pathogenesis have been identified in PD patients. This immune activation may be the cause of, rather than a response to, the observed neuronal loss. Parkinsonian motor symptoms include bradykinesia, muscular rigidity and resting tremor. The non-motor features include olfactory dysfunction, cognitive impairment, psychiatric symptoms and autonomic dysfunction. Microscopically, the specific degeneration of dopaminergic neurons in the substantia nigra and the presence of Lewy bodies, which are brain deposits containing a substantial amount of α-synuclein, have been recognized. The progression of Parkinson's disease is characterized by a worsening of motor features; however, as the disease progresses, there is an emergence of complications related to long-term symptomatic treatment. The available therapies for Parkinson's disease only treat the symptoms of the disease. A major goal of Parkinson's disease research is the development of disease-modifying drugs that slow or stop the neurodegenerative process. Drugs that enhance the intracerebral dopamine concentrations or stimulate dopamine receptors remain the mainstay treatment for motor symptoms. Immunomodulatory therapeutic strategies aiming to attenuate PD neurodegeneration have become an attractive option and warrant further investigation.

Keywords: Autoimmunity; Inflammation; Lewy bodies; Neurodegenerative disease; Olfactory dysfunction; Parkinson; α-Synuclein.

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Review
. 2020 Oct 17;15(1):59.
doi: 10.1186/s13024-020-00408-1.

Glycosphingolipids and neuroinflammation in Parkinson's disease

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Review

Glycosphingolipids and neuroinflammation in Parkinson's disease

Karim Belarbi et al. Mol Neurodegener. .
Free PMC article

Abstract

Parkinson's disease is a progressive neurodegenerative disease characterized by the loss of dopaminergic neurons of the nigrostriatal pathway and the formation of neuronal inclusions known as Lewy bodies. Chronic neuroinflammation, another hallmark of the disease, is thought to play an important role in the neurodegenerative process. Glycosphingolipids are a well-defined subclass of lipids that regulate crucial aspects of the brain function and recently emerged as potent regulators of the inflammatory process. Deregulation in glycosphingolipid metabolism has been reported in Parkinson's disease. However, the interrelationship between glycosphingolipids and neuroinflammation in Parkinson's disease is not well known. This review provides a thorough overview of the links between glycosphingolipid metabolism and immune-mediated mechanisms involved in neuroinflammation in Parkinson's disease. After a brief presentation of the metabolism and function of glycosphingolipids in the brain, it summarizes the evidences supporting that glycosphingolipids (i.e. glucosylceramides or specific gangliosides) are deregulated in Parkinson's disease. Then, the implications of these deregulations for neuroinflammation, based on data from human inherited lysosomal glycosphingolipid storage disorders and gene-engineered animal studies are outlined. Finally, the key molecular mechanisms by which glycosphingolipids could control neuroinflammation in Parkinson's disease are highlighted. These include inflammasome activation and secretion of pro-inflammatory cytokines, altered calcium homeostasis, changes in the blood-brain barrier permeability, recruitment of peripheral immune cells or production of autoantibodies.

Keywords: Gangliosides; Gaucher Disease; Glucocerebrosides; Glucosylceramides; Lipids; Microglia; Neurodegenerative Diseases; Parkinson Disease; Sphingolipids; Synucleinopathies.

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The authors declare that they have no competing interests.

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