Plasma-borne indicators of inflammasome activity in Parkinson’s disease patients

AbstractParkinson’s disease (PD) is a neurodegenerative disorder characterized by motor and non-motor symptoms and loss of dopaminergic neurons of the substantia nigra. Inflammation and cell death are recognized aspects of PD suggesting that strategies to monitor and modify these processes may improve the management of the disease. Inflammasomes are pro-inflammatory intracellular pattern recognition complexes that couple these processes. The NLRP3 inflammasome responds to sterile triggers to initiate pro-inflammatory processes characterized by maturation of inflammatory cytokines, cytoplasmic membrane pore formation, vesicular shedding, and if unresolved, pyroptotic cell death. Histologic analysis of tissues from PD patients and individuals with nigral cell loss but no diagnosis of PD identified elevated expression of inflammasome-related proteins and activation-related “speck” formation in degenerating mesencephalic tissues compared with controls. Based on previous reports of circulating inflammasome proteins in patients suffering from heritable syndromes caused by hyper-activation of the NLRP3 inflammasome, we evaluated PD patient plasma for evidence of inflammasome activity. Multiple circulating inflammasome proteins were detected almost exclusively in extracellular vesicles indicative of ongoing inflammasome activation and pyroptosis. Analysis of plasma obtained from a multi-center cohort identified elevated plasma-borne NLRP3 associated with PD status. Our findings are consistent with others indicating inflammasome activity in neurodegenerative disorders. Findings suggest mesencephalic inflammasome protein expression as a histopathologic marker of early-stage nigral degeneration and suggest plasma-borne inflammasome-related proteins as a potentially useful class of biomarkers for patient stratification and the detection and monitoring of inflammation in PD.

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

USURJ University of Saskatchewan Undergraduate Research Journal ◽

10.32396/usurj.v6i2.425 ◽

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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Pharmacological Blocker of NF-κb and Mitochondrial Ros Restrict NLRP3 Inflammasome Activation and Rescue Dopaminergic Neurons in Vitro and in Vivo Parkinson’s Disease

10.21203/rs.3.rs-260478/v1 ◽

2021 ◽

Author(s):

Sahabuddin Ahmed ◽

Samir Ranjan Panda ◽

Mohit Kwatra ◽

Bidya Dhar Sahu ◽

VGM Naidu

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Free Radicals ◽

Nlrp3 Inflammasome ◽

Nuclear Translocation ◽

Inflammasome Activation ◽

Mitochondrial Ros ◽

Nlrp3 Inflammasome Activation

Abstract Several activators of NLRP3 inflammasome have been described; however, the central mechanisms of NLRP3 inflammasome activation in brain microglia, especially at the activating step through free radical generation, still require further clarification. Hence the present study aimed to investigate the role of free radicals in activating NLRP3 inflammasome driven neurodegeneration and elucidated the neuroprotective role of perillyl alcohol (PA) in vitro and in vivo models of Parkinson’s disease. Initial priming of microglial cells with lipopolysaccharide (LPS) following treatment with hydrogen peroxide (H2O2) induces NF-κB translocation to nucleus with robust generation of free radicals that act as Signal 2 in augmenting NLRP3 inflammasome assembly and its downstream targets. PA treatment suppresses nuclear translocation of NF-κB and maintains cellular redox homeostasis in microglia that limits NLRP3 inflammasome activation along with processing active caspase-1, IL-1β and IL-18. To further correlates the in vitro study with in vivo MPTP model, treatment with PA also inhibits the nuclear translocation of NF-κB and downregulates the NLRP3 inflammasome activation. PA administration upregulates various antioxidant enzymes levels and restored the level of dopamine and other neurotransmitters in the striatum of the mice brain with improved behavioural activities. Additionally, treatment with Mito-TEMPO (a mitochondrial ROS inhibitor) was also seen to inhibit NLRP3 inflammasome and rescue dopaminergic neuron loss in the mice brain. Therefore, we conclude that NLRP3 inflammasome activation requires a signal from damaged mitochondria for its activation. Further pharmacological scavenging of free radicals restricts microglia activation and simultaneously supports neuronal survival via targeting NLRP3 inflammasome pathway in Parkinson’s disease.

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Olfactory Function and Diffusion Tensor Imaging as Markers of Mild Cognitive Impairment in Early Stages of Parkinson's Disease

Clinical EEG and Neuroscience ◽

10.1177/15500594211058263 ◽

2021 ◽

pp. 155005942110582

Author(s):

Sophie A. Stewart ◽

Laura Pimer ◽

John D. Fisk ◽

Benjamin Rusak ◽

Ron A. Leslie ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Cognitive Impairment ◽

Diffusion Tensor Imaging ◽

Mild Cognitive Impairment ◽

White Matter ◽

Neurodegenerative Disorder ◽

Diffusion Tensor ◽

Early Stage ◽

White Matter Integrity

Parkinson's disease (PD) is a neurodegenerative disorder that is typified by motor signs and symptoms but can also lead to significant cognitive impairment and dementia Parkinson's Disease Dementia (PDD). While dementia is considered a nonmotor feature of PD that typically occurs later, individuals with PD may experience mild cognitive impairment (PD-MCI) earlier in the disease course. Olfactory deficit (OD) is considered another nonmotor symptom of PD and often presents even before the motor signs and diagnosis of PD. We examined potential links among cognitive impairment, olfactory functioning, and white matter integrity of olfactory brain regions in persons with early-stage PD. Cognitive tests were used to established groups with PD-MCI and with normal cognition (PD-NC). Olfactory functioning was examined using the University of Pennsylvania Smell Identification Test (UPSIT) while the white matter integrity of the anterior olfactory structures (AOS) was examined using magnetic resonance imaging (MRI) diffusion tensor imaging (DTI) analysis. Those with PD-MCI demonstrated poorer olfactory functioning and abnormalities based on all DTI parameters in the AOS, relative to PD-NC individuals. OD and microstructural changes in the AOS of individuals with PD may serve as additional biological markers of PD-MCI.

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Systemic activation of NLRP3 inflammasome and plasma α-synuclein levels are correlated with motor severity and progression in Parkinson’s disease

Journal of Neuroinflammation ◽

10.1186/s12974-019-1670-6 ◽

2020 ◽

Vol 17 (1) ◽

Cited By ~ 13

Author(s):

Zheng Fan ◽

Yu-Ting Pan ◽

Zhi-Yuan Zhang ◽

Hui Yang ◽

Shu-Yue Yu ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Nlrp3 Inflammasome ◽

Plasma Levels ◽

Mononuclear Cells ◽

Inflammasome Activation ◽

Complete Evaluation ◽

Positive Correlation ◽

Caspase 1 ◽

Updrs Part

Abstract Background Emerging evidence indicates that inflammasome-induced inflammation plays a crucial role in the pathogenesis of Parkinson’s disease (PD). Several proteins including α-synuclein trigger the activation of NLRP3 inflammasome. However, few studies examined whether inflammasomes are activated in the periphery of PD patients and their possible value in the diagnosis or tracking of the progress of PD. The aim of this study was to determine the association between inflammasome-induced inflammation and clinical features in PD. Methods There were a total of 67 participants, including 43 patients with PD and 24 controls, in the study. Participants received a complete evaluation of motor and non-motor symptoms, including Hoehn and Yahr (H-Y) staging scale. Blood samples were collected from all participants. The protein and mRNA expression levels of inflammasomes subtypes and components in peripheral blood mononuclear cells (PBMCs) were determined using western blotting and RT-qPCR. We applied Meso Scale Discovery (MSD) immunoassay to measure the plasma levels of IL-1β and α-synuclein. Results We observed increased gene expression of NLRP3, ASC, and caspase-1 in PBMCs, and increased protein levels of NLRP3, caspase-1, and IL-1β in PD patients. Plasma levels of IL-1β were significantly higher in patients with PD compared with controls and have a positive correlation with H-Y stage and UPDRS part III scores. Furthermore, plasma α-synuclein levels were also increased in PD patients and have a positive correlation with both UPDRS part III scores and plasma IL-1β levels. Conclusions Our data demonstrated that the NLRP3 inflammasome is activated in the PBMCs from PD patients. The related inflammatory cytokine IL-1β and total α-synuclein in plasma were increased in PD patients than controls, and both of them presented a positive correlation with motor severity in patients with PD. Furthermore, plasma α-synuclein levels have a positive correlation with IL-1β levels in PD patients. All these findings suggested that the NLRP3 inflammasome activation-related cytokine IL-1β and α-synuclein could serve as non-invasive biomarkers to monitor the severity and progression of PD in regard to motor function.

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The Neuro-Protective Effects of the TSPO Ligands CB86 and CB204 on 6-OHDA-Induced PC12 Cell Death as an In Vitro Model for Parkinson’s Disease

Biology ◽

10.3390/biology10111183 ◽

2021 ◽

Vol 10 (11) ◽

pp. 1183

Author(s):

Sheelu Monga ◽

Nunzio Denora ◽

Valentino Laquintana ◽

Rami Yashaev ◽

Abraham Weizman ◽

...

Keyword(s):

Reactive Oxygen Species ◽

Parkinson’S Disease ◽

Parkinson's Disease ◽

Cell Death ◽

Neurodegenerative Disorder ◽

Reactive Oxygen ◽

Ros Generation ◽

Oxygen Species ◽

The Impact

Parkinson’s disease (PD) is a progressive neurodegenerative disorder which is characterized by the degeneration of dopaminergic neurons in substantia nigra (SN). Oxidative stress or reactive oxygen species (ROS) generation was suggested to play a role in this specific type of neurodegeneration. Therapeutic options which can target and counteract ROS generation may be of benefit. TSPO ligands are known to counteract with neuro-inflammation, ROS generation, apoptosis, and necrosis. In the current study, we investigated an in vitro cellular PD model by the assessment of 6-hydroxydopamine (6-OHDA, 80 µM)-induced PC12 neurotoxicity. Simultaneously to the exposure of the cells to 6-OHDA, we added the TSPO ligands CB86 and CB204 (25 µM each) and assessed the impact on several markers of cell death. The two ligands normalized significantly (57% and 52% respectively, from 44%; whereas the control was 68%) cell proliferation at different time points from 0–24 h. Additionally, we evaluated the effect of these two TSPO ligands on necrosis using propidium iodide (PI) staining and found that the ligands inhibited significantly the 6-OHDA-induced necrosis. As compared to control, the red count was increased up to 57-fold whereas CB86 and CB204 inhibited to 2.7-fold and 3.2-fold respectively. Necrosis was also analyzed by LDH assay which showed significant effect. Both assays demonstrated similar potent anti-necrotic effect of the two TSPO ligands. Reactive oxygen species (ROS) generation induced by 6-OHDA was also inhibited by the two TSPO ligand up to 1.3 and 1.5-fold respectively, as compared to 6-OHDA group. CB86 and CB204 inhibited also normalized the cell viability up to 1.8-fold after the exposure to 6-OHDA, as assessed by XTT assay. The two TSPO ligands also inhibited apoptosis significantly (1.3-fold for both) as assessed by apopxin green staining. In summary, it appears that the two TSPO ligands CB86 and CB204 can suppress cell death of PC12 induced by 6-OHDA. The results may be relevant to the use of these two TSPO ligands as therapeutic option neurodegenerative diseases like PD.

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Prediction of Parkinson’s Disease at Early Stage using Big Data Analytics

International Journal of Engineering and Advanced Technology - Regular Issue ◽

10.35940/ijeat.d8328.049420 ◽

2020 ◽

Vol 9 (4) ◽

pp. 2453-2459

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Big Data ◽

Data Analytics ◽

Clinical Medicine ◽

Neurodegenerative Disorder ◽

Early Stage ◽

Big Data Analytics ◽

Analytical Techniques ◽

Predictive Methods

Due to technological improvements in healthcare industry and clinical medicine, it requires to adapt new software techniques and tools to predict, diagnose and analyze disease patterns for making decisions in the early stage of disease. Parkinson’s disease is a neurodegenerative disorder. The PD damage the motor skills and may create speech problem and also affect the decision making process. Many people suffers with PD all over the world from many years. Day by day, the PD data has been increased, so the existing data mining predictive methods and tools does not give accurate results early for making decisions by doctors to save and increase the patient life period. Early PD symptoms can be detected by Big Data Analytics and proper medicine will be provided at the right time. In this paper, we are doing survey of predictive methods, Big Data Analytical techniques and also earlier researchers results presented.

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Semantic Memory and Lexical Availability in Parkinson’s Disease: A Statistical Learning Study

Frontiers in Aging Neuroscience ◽

10.3389/fnagi.2021.697065 ◽

2021 ◽

Vol 13 ◽

Author(s):

Juan F. Cardona ◽

Johan S. Grisales-Cardenas ◽

Catalina Trujillo-Llano ◽

Jesús A. Diazgranados ◽

Hugo F. Urquina ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Semantic Memory ◽

Classification Accuracy ◽

Neurodegenerative Disorder ◽

Early Stage ◽

Semantic Fluency ◽

Semantic Categories ◽

Semantic Fields ◽

Living Things

Parkinson’s disease (PD) is a neurodegenerative disorder that causes a progressive impairment in motor and cognitive functions. Although semantic fluency deficits have been described in PD, more specific semantic memory (SM) and lexical availability (LA) domains have not been previously addressed. Here, we aimed to characterize the cognitive performance of PD patients in a set of SM and LA measures and determine the smallest set of neuropsychological (lexical, semantic, or executive) variables that most accurately classify groups. Thirty early-stage non-demented PD patients (age 35–75, 10 females) and thirty healthy controls (age 36–76, 12 females) were assessed via general cognitive, SM [three subtests of the CaGi battery including living (i.e., elephant) and non-living things (i.e., fork)], and LA (eliciting words from 10 semantic categories related to everyday life) measures. Results showed that PD patients performed lower than controls in two SM global scores (picture naming and naming in response to an oral description). This impairment was particularly pronounced in the non-living things subscale. Also, the number of words in the LA measure was inferior in PD patients than controls, in both larger and smaller semantic fields, showing a more inadequate recall strategy. Notably, the classification algorithms indicated that the SM task had high classification accuracy. In particular, the denomination of non-living things had a classification accuracy of ∼80%. These results suggest that frontostriatal deterioration in PD leads to search strategy deficits in SF and the potential disruption in semantic categorization. These findings are consistent with the embodied view of cognition.

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Bushen-Yizhi Formula Alleviates Neuroinflammation via Inhibiting NLRP3 Inflammasome Activation in a Mouse Model of Parkinson’s Disease

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2018/3571604 ◽

2018 ◽

Vol 2018 ◽

pp. 1-12 ◽

Cited By ~ 4

Author(s):

Yousheng Mo ◽

Erjin Xu ◽

Renrong Wei ◽

Baoluu Le ◽

Lei Song ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Mouse Model ◽

Nlrp3 Inflammasome ◽

Molecular Mechanisms ◽

Neuronal Degeneration ◽

Interleukin 1 ◽

Inflammasome Activation ◽

Neuroprotective Effects ◽

Nlrp3 Inflammasome Activation

Parkinson’s disease (PD), the second most common neurodegenerative disease, is characterized by the progressive loss of dopaminergic neurons in the substantia nigra. Although the molecular mechanisms underlying dopaminergic neuronal degeneration in PD remain unclear, neuroinflammation is considered as the vital mediator in the pathogenesis and progression of PD. Bushen-Yizhi Formula (BSYZ), a traditional Chinese medicine, has been demonstrated to exert antineuroinflammation in our previous studies. However, it remains unclear whether BSYZ is effective for PD. Here, we sought to assess the neuroprotective effects and explore the underlying mechanisms of BSYZ in a 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine- (MPTP-) induced mouse model of PD. Our results indicate that BSYZ significantly alleviates the motor impairments and dopaminergic neuron degeneration of MPTP-treated mice. Furthermore, BSYZ remarkably attenuates microglia activation, inhibits NLPR3 activation, and decreases the levels of inflammatory cytokines in MPTP-induced mouse brain. Also, BSYZ inhibits NLRP3 activation and interleukin-1βproduction of the 1-methyl-4-phenyl-pyridinium (MPP+) stimulated BV-2 microglia cells. Taken together, our results indicate that BSYZ alleviates MPTP-induced neuroinflammation probably via inhibiting NLRP3 inflammasome activation in microglia. Collectively, BSYZ may be a potential therapeutic agent for PD and the related neurodegeneration diseases.

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Dopamine Signaling Modulates Microglial NLRP3 Inflammasome Activation: Implications for Parkinson’s Disease

10.21203/rs.3.rs-369002/v2 ◽

2021 ◽

Author(s):

Adrianne F. Pike ◽

Francesca Longhena ◽

Gaia Faustini ◽

Jean-Marc van Eik ◽

Iris Gombert ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Nlrp3 Inflammasome ◽

Critical Role ◽

Inflammasome Activation ◽

Human Microglia ◽

Dopaminergic Neurodegeneration ◽

Nlrp3 Inflammasome Activation ◽

Dopamine Signaling

Abstract Background: Parkinson’s disease (PD) is characterized by the loss of nigral dopaminergic neurons leading to impaired striatal dopamine signaling, α-synuclein- (α-syn-) rich inclusions, and neuroinflammation. Degenerating neurons are surrounded by activated microglia with increased secretion of interleukin-1β (IL-1β), driven largely by the NLRP3 inflammasome. A critical role for microglial NLRP3 inflammasome activation in the progression of both dopaminergic neurodegeneration and α-syn pathology has been demonstrated in parkinsonism mouse models. Fibrillar α-syn activates this inflammasome in mouse and human macrophages, and we have shown previously that the same holds true for primary human microglia. Dopamine blocks microglial NLRP3 inflammasome activation in the MPTP model, but its effects in this framework, highly relevant to PD, remain unexplored in primary human microglia and in other in vivo parkinsonism models. Methods: Biochemical techniques including quantification of IL-1β secretion and confocal microscopy were employed to gain insight into dopamine signaling-mediated inhibition of the NLRP3 inflammasome mechanism in primary human microglia and the SYN120 transgenic mouse model. Dopamine and related metabolites were applied to human microglia together with various inflammasome activating stimuli. The involvement of the receptors through which these catecholamines were predicted to act were assessed with agonists in both species. Results: We show in primary human microglia that dopamine, L-DOPA, and high extracellular K+, but not norepinephrine and epinephrine, block canonical, non-canonical, and α-syn-mediated NLRP3 inflammasome-driven IL-1β secretion. This suggests that dopamine acts as an inflammasome inhibitor in human microglia. Accordingly, we provide evidence that dopamine exerts its inhibitory effect through dopamine receptor D1 and D2 (DRD1 and DRD2) signaling. We also show that aged mice transgenic for human C-terminally truncated (1-120) α-syn (SYN120 tg mice) display increased NLRP3 inflammasome activation in comparison to WT mice that is diminished upon DRD1 agonism. Conclusions: Dopamine inhibits canonical, non-canonical, and α-syn-mediated activation of the NLRP3 inflammasome in primary human microglia, as does high extracellular K+. We suggest that dopamine serves as an endogenous repressor of the K+ efflux-dependent microglial NLRP3 inflammasome activation that contributes to dopaminergic neurodegeneration in PD, and that this reciprocation may account for the specific vulnerability of these neurons to disease pathology.

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

Frontiers in Aging Neuroscience ◽

10.3389/fnagi.2021.702639 ◽

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.

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