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

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.

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

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.

Parkinsonism, Parkinson’s disease, and related conditions

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.

scholarly journals Multi-parameter Behavioral Phenotyping of the MPP+ Model of Parkinson’s Disease in Zebrafish

2020 ◽  
Vol 14 ◽  
Author(s):  
Christian Christensen ◽  
Haraldur Þorsteinsson ◽  
Valerie Helene Maier ◽  
Karl Ægir Karlsson
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Dopaminergic Neurons ◽  
Animal Species ◽  
Drug Effects ◽  
Current Data ◽  
Motor Symptoms ◽  
Movement Frequency ◽  
Non Motor Symptoms ◽  
Drug Free

Parkinson’s disease (PD) has been modeled in several animal species using the neurotoxins 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its oxidized product 1-methyl-4-phenylpyridinium (MPP+). MPP+ selectively kills dopaminergic neurons in pars compacta of the substantia nigra, inducing parkinsonian symptoms in animals. Typically, neurotoxicity models of PD in zebrafish assess acute drug effects on locomotion. In the present study, we examined the lasting effects of MPP+ exposure and drug treatment in zebrafish larvae. Larvae were incubated in 500 μM MPP+, from 1 to 5 days post fertilization (dpf), followed by 24 h drug-free acclimation. At 6 dpf, the behavior was analyzed for locomotion, thigmotaxis, and sleep. Next, in separate assays we assessed the drug effects of brain injected glial cell-derived neurotrophic factor (GDNF) and 4-phenylbutyrate (PBA), co-incubated with MPP+. We show that MPP+ exposure consistently reduces swim distance, movement frequency, and cumulative time of movement; thus mimicking a parkinsonian phenotype of reduced movement. In contrast, MPP+ exposed larvae demonstrate reduced anxiety-like behavior and exhibit a sleep phenotype inconsistent with human PD: the larvae display longer sleep bouts, less sleep fragmentation, and more sleep. Previously reported rescuing effects of PBA were not replicated in this study. Moreover, whereas GDNF attenuated the sleep phenotype induced by MPP+, PBA augmented it. The current data suggest that MPP+ exposure generates a multifaceted phenotype in zebrafish and highlights that analyzing a narrow window of data can reveal effects that may be inconsistent with longer multi-parameter approaches. It further indicates that the model generally captures motor symptoms more faithfully than non-motor symptoms.

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.

Drosophila melanogaster a versatile model of Parkinson’s Disease

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.

Effect of Myricetin on the Loss of Dopaminergic Neurons in the Transgenic Drosophila Model of Parkinson’s Disease

2019 ◽  
Vol 14 (1) ◽  
pp. 58-64 ◽  
Author(s):  
Gulshan Ara ◽  
Mohammad Afzal ◽  
Smita Jyoti ◽  
Falaq Naz ◽  
Rahul ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Dopaminergic Neurons ◽  
Neuronal Damage ◽  
Radical Scavenging ◽  
Lewy Bodies ◽  
Dopamine Content ◽  
Drosophila Model ◽  
Dose Dependent ◽  
The Brain

Background: The formation of Lewy bodies is associated with the production of reactive oxygen species (ROS) and the neuronal damage specifically the dopaminergic neurons in the Parkinson’s disease patients. Hence any agent that could curtail the production of ROS /oxidative stress could act as a possible therapeutic agent thereby preventing the neuronal damage. </P><P> Method: In the present study, we first evaluated the antioxidant potential of myricetin by performing superoxide anion scavenging and diphenyl-picrylhydrazyl (DPPH) free radical scavenging assays. Myricetin at a final concentration of 10, 20 and 40&#181;M was mixed in diet and the PD flies were allowed to feed on it for 24 days. After 24 days of exposure, the dopamine content was estimated in brain and the immunohistochemistry was performed for the tyroxine hydroxylase activity on the brain sections from each group. </P><P> Results: Myricetin showed a dose-dependent increase in the antioxidative activity. The exposure of PD flies to 10, 20 and 40&#181;M of Myricetin not only showed a dose-dependent significant increase in the dopamine content compared to unexposed PD flies (p<0.05), but also prevented the loss of dopaminergic neurons in the brain of PD flies. </P><P> Conclusion: The results suggest that the antioxidative potential of myricetin is responsible for preventing the loss of dopaminergic neurons and dopamine content.

scholarly journals Animal models of Parkinson's disease: a guide to selecting the optimal model for your research

2021 ◽  
Author(s):  
Joana Lama ◽  
Yazead Buhidma ◽  
Edward JR Fletcher ◽  
Susan Duty
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Animal Models ◽  
Dopaminergic Neurons ◽  
Alpha Synuclein ◽  
Motor Symptoms ◽  
Multisystem Disorder ◽  
Wide Range ◽  
Non Motor Symptoms ◽  
Selection Of

Parkinson’s disease (PD) is a complex, multisystem disorder characterised by alpha synuclein pathology, degeneration of nigrostriatal dopaminergic neurons, multifactorial pathogenetic mechanisms and expression of a plethora of motor and non-motor symptoms. Animal models of PD have already been instructive in helping us unravel some of these aspects. However, much remains to be discovered, requiring continued interrogation by the research community. In contrast to the situation for many neurological disorders, PD benefits from of a wide range of available animal models (pharmacological, toxin, genetic and alpha-synuclein) but this makes selection of the optimal one for a given study difficult. This is especially so when a study demands a model that displays a specific combination of features. While many excellent reviews of animal models already exist, this review takes a different approach with the intention of more readily informing this decision-making process. We have considered each feature of PD in turn - aetiology, pathology, pathogenesis, motor dysfunctions and non-motor symptoms - highlighting those animal models that replicate each. By compiling easily accessible tables and figures, we aim to provide the reader with a simple, go-to resource for selecting the optimal animal model of PD to suit their research needs.

scholarly journals CuNA: Cumulant-based Network Analysis of genotype-phenotype associations in Parkinson's Disease

2021 ◽  
Author(s):  
Aritra Bose ◽  
Daniel E. Platt ◽  
Niina Haiminen ◽  
LAXMI PARIDA
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Network Analysis ◽  
Dopaminergic Neurons ◽  
Rating Scales ◽  
Clinical Phenotype ◽  
Motor Symptoms ◽  
Rna Seq ◽  
Phenotype Data ◽  
Non Motor Symptoms

Parkinson's Disease (PD) is a progressive neurodegenerative movement disorder characterized by loss of striatal dopaminergic neurons. Progression of PD is usually captured by a host of clinical features represented in different rating scales. PD diagnosis is associated with a broad spectrum of non-motor symptoms such as depression, sleep disorder as well as motor symptoms such as movement impairment, etc. The variability within the clinical phenotype of PD makes detection of the genes associated with early onset PD a difficult task. To address this issue, we developed CuNA, a cumulant-based network analysis algorithm that creates a network from higher-order relationships between eQTLs and phenotypes as captured by cumulants. We also designed a multi-omics simulator, CuNAsim to test CuNA's qualitative accuracy. CuNA accurately detects communities of clinical phenotypes and finds genes associated with them. When applied on PD data, we find previously unreported genes INPP5J, SAMD1 and OR4K13 associated with symptoms of PD affecting the kidney, muscles and olfaction. CuNA provides a framework to integrate and analyze RNA-seq, genotype and clinical phenotype data from complex diseases for more targeted diagnostic and therapeutic solutions in personalized medicine. CuNA and CuNAsim binaries are available upon request.

scholarly journals Mitochondrial Dysfunction andα-Synuclein Synaptic Pathology in Parkinson’s Disease: Who’s on First?

2015 ◽  
Vol 2015 ◽  
pp. 1-10 ◽  
Author(s):  
Michela Zaltieri ◽  
Francesca Longhena ◽  
Marina Pizzi ◽  
Cristina Missale ◽  
PierFranco Spano ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Mitochondrial Dysfunction ◽  
Dopaminergic Neurons ◽  
Lewy Bodies ◽  
Nigrostriatal System ◽  
Primary Role ◽  
Lewy Neurites ◽  
Synaptic Pathology ◽  
Lines Of Evidence

Parkinson’s disease (PD) is the most common neurodegenerative movement disorder. Its characteristic neuropathological features encompass the loss of dopaminergic neurons of the nigrostriatal system and the presence of Lewy bodies and Lewy neurites. These are intraneuronal and intraneuritic proteinaceous insoluble aggregates whose main constituent is the synaptic proteinα-synuclein. Compelling lines of evidence indicate that mitochondrial dysfunction andα-synuclein synaptic deposition may play a primary role in the onset of this disorder. However, it is not yet clear which of these events may come first in the sequel of processes leading to neurodegeneration. Here, we reviewed data supporting either thatα-synuclein synaptic deposition precedes and indirectly triggers mitochondrial damage or that mitochondrial deficits lead to neuronal dysfunction andα-synuclein synaptic accumulation. The present overview shows that it is still difficult to establish the exact temporal sequence and contribution of these events to PD.

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