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

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.

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

2020 ◽  
Author(s):  
Sara K. Nissen ◽  
Sara A. Ferreira ◽  
Claudia Schulte ◽  
Kalpana Shrivastava ◽  
Dorle Hennig ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Immune Cells ◽  
Acute Phase Proteins ◽  
Neurodegenerative Disorder ◽  
Alpha Synuclein ◽  
Cognitive Capacity ◽  
Soluble Form ◽  
Immune Biomarkers ◽  
The Brain

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.

scholarly journals Periphery and brain, innate and adaptive immunity in Parkinson’s disease

2021 ◽  
Vol 141 (4) ◽  
pp. 527-545 ◽  
Author(s):  
Ashley S. Harms ◽  
Sara A. Ferreira ◽  
Marina Romero-Ramos
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Nervous System ◽  
Immune System ◽  
Adaptive Immunity ◽  
Neurodegenerative Disorder ◽  
Neuronal Degeneration ◽  
Adaptive Immune System ◽  
Alpha Synuclein ◽  
Adaptive Immune

AbstractParkinson’s disease (PD) is a neurodegenerative disorder where alpha-synuclein plays a central role in the death and dysfunction of neurons, both, in central, as well as in the peripheral nervous system. Besides the neuronal events observed in patients, PD also includes a significant immune component. It is suggested that the PD-associated immune response will have consequences on neuronal health, thus opening immunomodulation as a potential therapeutic strategy in PD. The immune changes during the disease occur in the brain, involving microglia, but also in the periphery with changes in cells of the innate immune system, particularly monocytes, as well as those of adaptive immunity, such as T-cells. This realization arises from multiple patient studies, but also from data in animal models of the disease, providing strong evidence for innate and adaptive immune system crosstalk in the central nervous system and periphery in PD. Here we review the data showing that alpha-synuclein plays a crucial role in the activation of the innate and adaptive immune system. We will also describe the studies suggesting that inflammation in PD includes early changes in innate and adaptive immune cells that develop dynamically through time during disease, contributing to neuronal degeneration and symptomatology in patients. This novel finding has contributed to the definition of PD as a multisystem disease that should be approached in a more integratory manner rather than a brain-focused classical approach.

Peripheral Immunity, Immunoaging and Neuroinflammation in Parkinson’s Disease

2019 ◽  
Vol 26 (20) ◽  
pp. 3719-3753 ◽  
Author(s):  
Natasa Kustrimovic ◽  
Franca Marino ◽  
Marco Cosentino
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Immune System ◽  
Neurodegenerative Disorder ◽  
Neurodegenerative Process ◽  
Progressive Degeneration ◽  
Cytokine Levels ◽  
Inflammatory Phenotype ◽  
Immune Challenges

:Parkinson’s disease (PD) is the second most common neurodegenerative disorder among elderly population, characterized by the progressive degeneration of dopaminergic neurons in the midbrain. To date, exact cause remains unknown and the mechanism of neurons death uncertain. It is typically considered as a disease of central nervous system (CNS). Nevertheless, numerous evidence has been accumulated in several past years testifying undoubtedly about the principal role of neuroinflammation in progression of PD. Neuroinflammation is mainly associated with presence of activated microglia in brain and elevated levels of cytokine levels in CNS. Nevertheless, active participation of immune system as well has been noted, such as, elevated levels of cytokine levels in blood, the presence of auto antibodies, and the infiltration of T cell in CNS. Moreover, infiltration and reactivation of those T cells could exacerbate neuroinflammation to greater neurotoxic levels. Hence, peripheral inflammation is able to prime microglia into pro-inflammatory phenotype, which can trigger stronger response in CNS further perpetuating the on-going neurodegenerative process.:In the present review, the interplay between neuroinflammation and the peripheral immune response in the pathobiology of PD will be discussed. First of all, an overview of regulation of microglial activation and neuroinflammation is summarized and discussed. Afterwards, we try to collectively analyze changes that occurs in peripheral immune system of PD patients, suggesting that these peripheral immune challenges can exacerbate the process of neuroinflammation and hence the symptoms of the disease. In the end, we summarize some of proposed immunotherapies for treatment of PD.

scholarly journals Treating Parkinson’s Disease with Antibodies: Previous Studies and Future Directions

2020 ◽  
pp. 1-22
Author(s):  
Anne-Marie Castonguay ◽  
Claude Gravel ◽  
Martin Lévesque
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Disorder ◽  
Passive Immunization ◽  
Lewy Bodies ◽  
Gene Mutations ◽  
Alpha Synuclein ◽  
Multiple Sources ◽  
Immunization Strategies ◽  
A Cell

Parkinson’s disease is a neurodegenerative disorder mainly characterized by the degeneration of dopaminergic neurons in the substantia nigra. Degenerating neurons contain abnormal aggregates called Lewy bodies, that are predominantly composed of the misfolded and/or mutated alpha-synuclein protein. Post-translational modifications, cellular stress, inflammation and gene mutations are thought to trigger its pathological misfolding and aggregation. With alpha-synuclein pathology being strongly associated with dopaminergic neuronal toxicity, strategies aimed to reduce its burden are expected to be beneficial in slowing disease progression. Moreover, multiple sources of evidence suggest a cell-to-cell transmission of pathological alpha-synuclein in a prion-like manner. Therefore, antibodies targeting extra- or intracellular alpha-synuclein could be efficient in limiting the aggregation and transmission. Several active and passive immunization strategies have been explored to target alpha-synuclein. Here, we summarize immunotherapeutic approaches that were tested in pre-clinical or clinical studies in the last two decades in an attempt to treat Parkinson’s disease.

Effect of Cabergoline on Cognitive Impairments in Transgenic Drosophila Model of Parkinson’s Disease

2020 ◽  
Vol 17 (10) ◽  
pp. 1261-1269
Author(s):  
Yasir Hasan Siddique ◽  
Rahul ◽  
Mantasha Idrisi ◽  
Mohd. Shahid
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Dopaminergic Neurons ◽  
Neurodegenerative Disorder ◽  
Cognitive Impairments ◽  
Alpha Synuclein ◽  
Substantia Nigra Pars Compacta ◽  
Positive Interaction ◽  
Drosophila Model ◽  
Transgenic Drosophila

Background: Parkinson’s disease is a common neurodegenerative disorder characterized by selective loss of dopaminergic neurons in the substantia nigra pars compacta. Introduction: The effects of alpha synuclein, parkin mutation and pharmacological agents have been studied in the Drosophila model. Methods: The effect of cabergoline was studied on the cognitive impairments exhibited by the transgenic Drosophila expressing human alpha-synuclein in the neurons. The PD flies were allowed to feed on the diet having 0.5, 1 and 1.5 μM of cabergoline. Results and Discussion: The exposure of cabergoline not only showed a dose-dependent significant delay in the cognitive impairments but also prevented the loss of dopaminergic neurons. Molecular docking studies showed the positive interaction between cabergoline and alpha-synuclein. Conclusion: The results suggest a protective effect of cabergoline against the cognitive impairments.

scholarly journals Integration of functional genomics data to uncover cell type-specific pathways affected in Parkinson's disease

2021 ◽  
Author(s):  
Viola Volpato
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Disorder ◽  
Disease Risk ◽  
Late Onset ◽  
Alpha Synuclein ◽  
Biological Information ◽  
Cell Type ◽  
Risk Variants ◽  
Cell Type Specific

Parkinson's disease (PD) is the second most prevalent late-onset neurodegenerative disorder worldwide after Alzheimer's disease for which available drugs only deliver temporary symptomatic relief. Loss of dopaminergic neurons (DaNs) in the substantia nigra and intracellular alpha-synuclein inclusions are the main hallmarks of the disease but the events that cause this degeneration remain uncertain. Despite cell types other than DaNs such as astrocytes, microglia and oligodendrocytes have been recently associated with the pathogenesis of PD, we still lack an in-depth characterisation of PD-affected brain regions at cell-type resolution that could help our understanding of the disease mechanisms. Nevertheless, publicly available large-scale brain-specific genomic, transcriptomic and epigenomic datasets can be further exploited to extract different layers of cell type-specific biological information for the reconstruction of cell type-specific transcriptional regulatory networks. By intersecting disease risk variants within the networks, it may be possible to study the functional role of these risk variants and their combined effects at cell type- and pathway levels, that, in turn, can facilitate the identification of key regulators involved in disease progression, which are often potential therapeutic targets.

scholarly journals Alpha-Synuclein as a Biomarker of Parkinson’s Disease: Good, but Not Good Enough

2021 ◽  
Vol 13 ◽  
Author(s):  
Upasana Ganguly ◽  
Sukhpal Singh ◽  
Soumya Pal ◽  
Suvarna Prasad ◽  
Bimal K. Agrawal ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Movement Disorders ◽  
Neurodegenerative Disorder ◽  
Early Stage ◽  
Motor Impairment ◽  
The Elderly ◽  
Alpha Synuclein ◽  
Cross Sectional ◽  
Peripheral Tissues

Parkinson’s disease (PD) is the second most common neurodegenerative disorder of the elderly, presenting primarily with symptoms of motor impairment. The disease is diagnosed most commonly by clinical examination with a great degree of accuracy in specialized centers. However, in some cases, non-classical presentations occur when it may be difficult to distinguish the disease from other types of degenerative or non-degenerative movement disorders with overlapping symptoms. The diagnostic difficulty may also arise in patients at the early stage of PD. Thus, a biomarker could help clinicians circumvent such problems and help them monitor the improvement in disease pathology during anti-parkinsonian drug trials. This review first provides a brief overview of PD, emphasizing, in the process, the important role of α-synuclein in the pathogenesis of the disease. Various attempts made by the researchers to develop imaging, genetic, and various biochemical biomarkers for PD are then briefly reviewed to point out the absence of a definitive biomarker for this disorder. In view of the overwhelming importance of α-synuclein in the pathogenesis, a detailed analysis is then made of various studies to establish the biomarker potential of this protein in PD; these studies measured total α-synuclein, oligomeric, and post-translationally modified forms of α-synuclein in cerebrospinal fluid, blood (plasma, serum, erythrocytes, and circulating neuron-specific extracellular vesicles) and saliva in combination with certain other proteins. Multiple studies also examined the accumulation of α-synuclein in various forms in PD in the neural elements in the gut, submandibular glands, skin, and the retina. The measurements of the levels of certain forms of α-synuclein in some of these body fluids or their components or peripheral tissues hold a significant promise in establishing α-synuclein as a definitive biomarker for PD. However, many methodological issues related to detection and quantification of α-synuclein have to be resolved, and larger cross-sectional and follow-up studies with controls and patients of PD, parkinsonian disorders, and non-parkinsonian movement disorders are to be undertaken.

scholarly journals Alpha-synuclein levels modulate seeding and aggregation in cultured cells

2021 ◽  
Author(s):  
Eftychia Vasili ◽  
Antonio Dominguez-Meijide ◽  
Manuel Flores-León ◽  
Mohammed Al-Azzani ◽  
Angeliki Kanellidi ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cell Lines ◽  
Molecular Mechanisms ◽  
Cultured Cells ◽  
Neurodegenerative Disorder ◽  
Alpha Synuclein ◽  
Lewy Neurites ◽  
Stable Cell Lines ◽  
The Impact

Abstract Background Parkinson's disease is a progressive neurodegenerative disorder characterized by the accumulation of misfolded alpha-synuclein in intraneuronal inclusions known as Lewy bodies and Lewy neurites. Multiple studies strongly implicate the levels of alpha-synuclein as a major risk factor for the onset and progression of Parkinson’s disease. alpha-Synuclein pathology spreads progressively throughout interconnected brain regions but the precise molecular mechanisms underlying alpha-synuclein spreading and accumulation remain obscure. Methods Here, using stable cell lines expressing alpha-synuclein, we examined the correlation between endogenous alpha-synuclein levels and the seeding propensity by exogenous alpha-synuclein pre-formed fibrils. We applied biochemical approaches and imaging methods in stable cell lines expressing alpha-synuclein and in primary neurons to determine the impact of alpha-synuclein expression levels on seeding and aggregation. Results Our results indicate that alpha-synuclein levels define the pattern and severity of aggregation and the extent of p-alpha-synuclein deposition, likely explaining the selective vulnerability of different cell types in synucleinopathies. Conclusions The elucidation of the cellular processes involved in the pathological aggregation of alpha-synuclein will enable the identification of novel targets and the development of therapeutic strategies for Parkinson's disease and other synucleinopathies.

scholarly journals Therapeutic potential of methylxanthine drug on alpha synuclein protein in Parkinson's disease

2021 ◽  
Author(s):  
Nishant Kumar Rana ◽  
Neha Srivastava ◽  
Bhupendra Kumar ◽  
Abhishek Pathak ◽  
Vijay Nath Mishra
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Disorder ◽  
Therapeutic Potential ◽  
Enrichment Analysis ◽  
Alpha Synuclein ◽  
Target Protein ◽  
Functional Enrichment ◽  
Glutamate Excitotoxicity ◽  
In Silico Docking

Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer. It exists in sporadic (90 to 95%) and familial (5 to 10%) form. Its pathogenesis is due to oxidative stress, glutamate excitotoxicity, protein aggregation, neuroinflammation and neurodegeneration. There is currently no cure for this disease. The protein- protein interaction and gene ontology/functional enrichment analysis have been performed to find out the prominent interactor protein and shared common biological pathways, especially PD pathway. Further in silico docking analysis was performed on target protein to investigate the prominent drug molecule for PD. Through computational molecular virtual screening of small molecules from selected twelve natural compounds, and among these compounds methylxanthine was shown to be prominent inhibitor to SNCA protein that ultimately prevent PD. The interaction of methylxanthine compound with the target protein SNCA suggested that, it interacted with prominent binding site with good docking score and might be involved in blocking the binding of neuroinducing substances like: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to SNCA protein. Thus methylxanthine compounds can be explored as promising drugs for the prevention of Parkinson's disease.

scholarly journals Alpha-synuclein promotes dopaminergic neuron death in Parkinson’s disease through microglial and NLRP3 activation

2020 ◽  
Vol 6 (2) ◽  
Author(s):  
Sarah Klein
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Nlrp3 Inflammasome ◽  
Neurodegenerative Disorder ◽  
Alpha Synuclein ◽  
Substantia Nigra Pars Compacta ◽  
Motor Deficits ◽  
Inflammasome Activation ◽  
Neuron Death ◽  
Nlrp3 Inflammasome Activation

Parkinson’s disease (PD) is a progressive neurodegenerative disorder that involves the death of dopaminergic neurons in the substantia nigra pars compacta (SNpc). After neuronal death, the subsequent reduction of dopamine levels in the brain induces motor deficits characteristic of this hypokinetic disorder. Although there is currently no known cause of PD, alpha-synuclein appears to have a prominent role in both microglial and NLRP3 inflammasome activation. The consequential release of the pro-inflammatory cytokine interleukin-1β (IL-1β) has been demonstrated to be responsible for neuroinflammation and neurodegeneration in PD. The present review highlights the role of alpha-synuclein aggregates in Parkinson’s disease pathogenesis. The PD alpha-synuclein preformed fibril (PFF) animal model permits the specific targeting of alpha-synuclein-mediated microglial and NLRP3 inflammasome activation in newly designed therapies. Studies using this model suggest MCC950 and its analogs as a potential new treatment to prevent neurodegeneration in Parkinson’s disease.

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