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

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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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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α-Synuclein in Parkinson’s Disease: Does a Prion-Like Mechanism of Propagation from Periphery to the Brain Play a Role?

The Neuroscientist ◽

10.1177/1073858420943180 ◽

2020 ◽

pp. 107385842094318

Author(s):

Huimin Zheng ◽

Changhe Shi ◽

Haiyang Luo ◽

Liyuan Fan ◽

Zhihua Yang ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Dopaminergic Neurons ◽

Lewy Bodies ◽

Cellular Level ◽

Motor Symptoms ◽

Lewy Neurites ◽

Growing Body ◽

Non Motor Symptoms ◽

The Brain

Parkinson’s disease (PD) is one of the most common neurodegenerative diseases, defined as motor and non-motor symptoms associated with the loss of dopaminergic neurons and a decreased release of dopamine (DA). Currently, PD patients are believed to have a neuropathological basis denoted by the presence of Lewy bodies (LBs) or Lewy neurites (LNs), which mostly comprise α-synuclein (α-syn) inclusions. Remarkably, there is a growing body of evidence indicating that the inclusions undergo template-directed aggregation and propagation via template-directed among the brain and peripheral organs, mainly in a prion-like manner. Interestingly, some studies reported that an integral loop was reminiscent of the mechanism of Parkinson’s disease, denoting that α-syn as prionoid was transmitted from the periphery to the brain via specific pathways. Also the systematic life cycle of α-syn in the cellular level is illustrated. In this review, we critically assess landmark evidence in the field of Parkinson’s disease with a focus on the genesis and prion-like propagation of the α-syn pathology. The anatomical and cell-to-cell evidences are discussed to depict the theory behind the propagation and transferred pathways. Furthermore, we highlight effective therapeutic perspectives and clinical trials targeting prion-like mechanisms. Major controversies surrounding this topic are also discussed.

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Parkinsonism, Parkinson’s disease, and related conditions

Oxford Textbook of Geriatric Medicine ◽

10.1093/med/9780198701590.003.0116 ◽

2017 ◽

pp. 897-906

Author(s):

John V. Hindle ◽

Sion Jones ◽

Glesni Davies

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Older People ◽

Lewy Bodies ◽

Cell Loss ◽

Brain Regions ◽

Motor Symptoms ◽

Advanced Care Planning ◽

Non Motor Symptoms

Parkinson’s disease (PD) is a progressive neurodegenerative condition characterized clinically by fatiguable bradykinesia, rigidity and tremor and pathologically by deposition of Lewy bodies and cell loss in the substantia nigra and other brain regions. Parkinsonism is the term used to describe the clinical features of conditions resembling PD. Their management requires specialist assessment and a multidisciplinary approach. Levodopa remains the mainstay of treatment for PD. Although other treatments are used, older people are more sensitive to their side effects. Non-motor symptoms, particularly neuropsychiatric problems, significantly impact quality of life and need special consideration in older people. Towards the later stage of the disease, management can be complex, and should involve advanced care planning.

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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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Transgenic mice expressing human alpha-synuclein in noradrenergic neurons develop locus coeruleus pathology and non-motor features of Parkinson’s disease

10.1101/857987 ◽

2019 ◽

Author(s):

LM Butkovich ◽

MC Houser ◽

T Chalermpalanupap ◽

KA Porter-Stransky ◽

AF Iannitelli ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Transgenic Mice ◽

Locus Coeruleus ◽

Transgenic Mouse ◽

Alpha Synuclein ◽

Striatal Dopamine ◽

Motor Symptoms ◽

Age Dependent ◽

Non Motor Symptoms

AbstractDegeneration of locus coeruleus (LC) neurons and dysregulation of noradrenergic signaling are ubiquitous features of Parkinson’s disease (PD). The LC is among the first brain regions affected by α-synuclein (asyn) pathology, yet how asyn affects these neurons remains unclear. LC-derived norepinephrine (NE) can stimulate neuroprotective mechanisms and modulate immune cells, while dysregulation of NE neurotransmission may exacerbate disease progression, particularly non-motor symptoms, and contribute to the chronic neuroinflammation associated with PD pathology. Although transgenic mice overexpressing asyn have previously been developed, transgene expression is usually driven by pan-neuronal promoters and thus has not been selectively targeted to LC neurons. Here we report a novel transgenic mouse expressing human wild-type asyn under control of the noradrenergic-specific dopamine β-hydroxylase promoter. These mice developed oligomeric and conformation-specific asyn in LC neurons, alterations in hippocampal and LC microglial abundance, upregulated GFAP expression, degeneration of LC fibers, decreased striatal dopamine (DA) metabolism, and age-dependent behaviors reminiscent of non-motor symptoms of PD that were rescued by adrenergic receptor antagonists. These mice provide novel insights into how asyn pathology affects LC neurons and how central noradrenergic dysfunction may contribute to early PD pathophysiology.Significance statementα-synuclein (asyn) pathology and loss of neurons in the locus coeruleus (LC) are two of the most ubiquitous neuropathologic features of Parkinson’s disease (PD). Dysregulated NE neurotransmission is associated with the non-motor symptoms of PD including sleep disturbances, emotional changes such as anxiety and depression, and cognitive decline. Importantly, loss of central NE may contribute to the chronic inflammation in, and progression of, PD. We have generated a novel transgenic mouse expressing human asyn in LC neurons to investigate how increased asyn expression affects the function of the central noradrenergic transmission and associated behaviors. We report cytotoxic effects of oligomeric and conformation-specific asyn, astrogliosis, LC fiber degeneration, disruptions in striatal dopamine metabolism, and age-dependent alterations in non-motor behaviors without inclusions.

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Modelling Non-motor Symptoms of Parkinson’s Disease: AAV Mediated Overexpression of Alpha-synuclein in Rat Hippocampus and Basal Ganglia

Turkish Journal Of Neurology ◽

10.4274/tnd.2020.22308 ◽

2020 ◽

Vol 26 (4) ◽

pp. 322-329

Author(s):

Sevgi Uğur Mutluay ◽

Elif Çınar ◽

Gül Yalçın Çakmaklı ◽

Ayşe Ulusoy ◽

Bülent Elibol ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Basal Ganglia ◽

Alpha Synuclein ◽

Rat Hippocampus ◽

Motor Symptoms ◽

Non Motor Symptoms

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α-synuclein pathogenesis in hiPSC models of Parkinson’s Disease

Neuronal Signaling ◽

10.1042/ns20210021 ◽

2021 ◽

Author(s):

Leo R Quinlan ◽

Jara Maria Baena-Montes ◽

Sahar Avazzadeh

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Disease Modeling ◽

Viral Vector ◽

Neurodegenerative Disorder ◽

Current Knowledge ◽

Lewy Bodies ◽

Model Systems ◽

The Brain

α-synuclein is an increasingly prominent player in the pathology of a variety of neurodegenerative conditions. Parkinson’s disease (PD) is a neurodegenerative disorder that affects mainly the dopaminergic neurons in the substantia nigra of the brain. Typical of PD pathology is the finding of protein aggregations termed ‘Lewy bodies’ in the brain regions affected. α-synuclein is implicated in many disease states including dementia with Lewy bodies and Alzheimer’s disease. However, PD is the most common synucleinopathy and continues to be a significant focus of PD research in terms of the α-synuclein Lewy body pathology. Mutations in several genes are associated with PD development including SNCA, which encodes α-synuclein. A variety of model systems have been employed to study α-synuclein physiology and pathophysiology in an attempt to relate more closely to PD pathology. These models include cellular and animal system exploring transgenic technologies, viral vector expression and knockdown approaches, and models to study the potential prion protein-like effects of α-synuclein. The current review focuses on human induced pluripotent stem cell (iPSC) models with a specific focus on mutations or multiplications of the SNCA gene. iPSCs are a rapidly evolving technology with huge promise in the study of normal physiology and disease modeling in vitro. The ability to maintain a patient's genetic background and replicate similar cell phenotypes make iPSCs a powerful tool in the study of neurological diseases. This review focus on the current knowledge about α-synuclein physiological function as well as its role in PD pathogenesis based on human iPSC models.

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Drosophila melanogaster a versatile model of Parkinson’s Disease

CNS & Neurological Disorders - Drug Targets ◽

10.2174/1871527320666210208125912 ◽

2021 ◽

Vol 20 ◽

Author(s):

Falaq Naz ◽

Yasir Hasan Siddique

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Drosophila Melanogaster ◽

Lewy Bodies ◽

Substantia Nigra Pars Compacta ◽

Maintenance Cost ◽

The Novel ◽

Life Threatening ◽

Non Motor Symptoms ◽

The Brain

: Parkinson's Disease (PD) is one of the most prevalent, recurrent and life-threatening neurodegenerative disease. However, the precise mechanism underlying this disease is not yet clearly understood. For understanding the pathogenesis of PD, it is essential to identify the symptoms along with the novel biological markers and to develop strategies which could lead towards the development of effective therapy. PD is associated with Lewy bodies (LBs) formation and the loss of dopaminergic neurons in the substantia nigra pars compacta of mid brain region. For the improvement in treatment strategiesas well as understanding the pathophysiology of the PD in number ofanimal models have been introduced that can recapitulatethe pathophysiology, motor and non-motor symptoms of PD. In contrast to mammalian models like rodents, mice and monkey, Drosophila is easy to handle as well as it maintenance cost is low.Due to the anatomical differencesin the brain and other major organsof human and fly,the issues of standardizing the methods or experiments to analyze behavioral aspects (walking, writhing, eating and sleeping) are difficult in flies. Thepresent review highlights the studies carried out for PD since 2000, using Drosophila melanogaster.

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Microbiome, Parkinson’s Disease and Molecular Mimicry

Cells ◽

10.3390/cells8030222 ◽

2019 ◽

Vol 8 (3) ◽

pp. 222 ◽

Cited By ~ 13

Author(s):

Fabiana Miraglia ◽

Emanuela Colla

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Molecular Mimicry ◽

Current Knowledge ◽

Lewy Bodies ◽

Alpha Synuclein ◽

Causative Role ◽

Olfactory Bulbs ◽

Host Interactions ◽

Aggregation Propensity

Parkinson’s Disease (PD) is typically classified as a neurodegenerative disease affecting the motor system. Recent evidence, however, has uncovered the presence of Lewy bodies in locations outside the CNS, in direct contact with the external environment, including the olfactory bulbs and the enteric nervous system. This, combined with the ability of alpha-synuclein (αS) to propagate in a prion-like manner, has supported the hypothesis that the resident microbial community, commonly referred to as microbiota, might play a causative role in the development of PD. In this article, we will be reviewing current knowledge on the importance of the microbiota in PD pathology, concentrating our investigation on mechanisms of microbiota-host interactions that might become harmful and favor the onset of PD. Such processes, which include the secretion of bacterial amyloid proteins or other metabolites, may influence the aggregation propensity of αS directly or indirectly, for example by favoring a pro-inflammatory environment in the gut. Thus, while the development of PD has not yet being associated with a unique microbial species, more data will be necessary to examine potential harmful interactions between the microbiota and the host, and to understand their relevance in PD pathogenesis.

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