The Involvement of Neuroinflammation in the Onset and Progression of Parkinson's Disease.
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ABSTRACT:
SUBMITTER: Jurcau A
PROVIDER: S-EPMC10573049 | biostudies-literature | 2023 Sep
REPOSITORIES: biostudies-literature
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The Involvement of Neuroinflammation in the Onset and Progression of Parkinson's Disease.
Jurcau Anamaria A Andronie-Cioara Felicia Liana FL Nistor-Cseppento Delia Carmen DC Pascalau Nicoleta N Rus Marius M Vasca Elisabeta E Jurcau Maria Carolina MC
International journal of molecular sciences 20230926 19
Parkinson's disease is a neurodegenerative disease exhibiting the fastest growth in incidence in recent years. As with most neurodegenerative diseases, the pathophysiology is incompletely elucidated, but compelling evidence implicates inflammation, both in the central nervous system and in the periphery, in the initiation and progression of the disease, although it is not yet clear what triggers this inflammatory response and where it begins. Gut dysbiosis seems to be a likely candidate for the ...[more]
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Project description:Neuroinflammation is one of the most important processes involved in the pathogenesis of Parkinson's disease (PD). The current concept of neuroinflammation comprises an inflammation process, which occurs in the central nervous system due to molecules released from brain-resident and/or blood-derived immune cells. Furthermore, the evidence of the contribution of systemic delivered molecules to the disease pathogenesis, such as the gut microbiota composition, has been increasing during the last years. Under physiological conditions, microglia and astrocytes support the well-being and well-function of the brain through diverse functions, including neurotrophic factor secretion in both intact and injured brain. On the other hand, genes that cause PD are expressed in astrocytes and microglia, shifting their neuroprotective role to a pathogenic one, contributing to disease onset and progression. In addition, growth factors are a subset of molecules that promote cellular survival, differentiation and maturation, which are critical signaling factors promoting the communication between cells, including neurons and blood-derived immune cells. We summarize the potential targeting of astrocytes and microglia and the systemic contribution of the gut microbiota in neuroinflammation process archived in PD.
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Project description: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.
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Project description:Early onset Parkinson’s Disease (onset <50 years) accounts for between 10-20 percent of all patients. While some of these cases are associated with specific mutations, the majority are sporadic where the cause is unknown. We generated induced pluripotent stem cells from sporadic early onset patients and differentiated them to dopamine neurons. At early stages in culture (30 days) we found significant elevations in soluble α-synuclein protein levels when compared to controls. This was associated with reductions in lysosomal membrane proteins such as LAMP1 and an increase in phosphorylated protein kinase C-α (p-PKCα). Testing activators of lysosomal function showed that specific phorbal esters reduced both α-synuclein and p-PKCα levels and increased LAMP1 expression. Interestingly, very low doses of the drug PEP005 were able to reduce α-synuclein levels without affecting p-PKCα. Similar effects of PEP005 on α-synuclein expression were seen following infusion into the mouse brain. Our data show that early onset sporadic Parkinson’s Disease can be accurately predicted using a ratio of α-synuclein and p-PKCα in dopamine neural cultures derived from patient iPSC’s and that specific phorbal esters can alter both biomarkers making these drugs promising candidates to treat Parkinson’s Disease.
2019-12-06 | PXD011326 | Pride
Project description:Parkinson's disease (PD) is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the appearance of ?-synuclein insoluble aggregates known as Lewy bodies. Neurodegeneration is accompanied by neuroinflammation mediated by cytokines and chemokines produced by the activated microglia. Several studies demonstrated that such an inflammatory process is an early event, and contributes to oxidative stress and mitochondrial dysfunctions. ?-synuclein fibrillization and aggregation activate microglia and contribute to disease onset and progression. Mutations in different genes exacerbate the inflammatory phenotype in the monogenic compared to sporadic forms of PD. Positron Emission Tomography (PET) and Single Photon Emission Computed Tomography (SPECT) with selected radiopharmaceuticals allow in vivo imaging of molecular modifications in the brain of living subjects. Several publications showed a reduction of dopaminergic terminals and dopamine (DA) content in the basal ganglia, starting from the early stages of the disease. Moreover, non-dopaminergic neuronal pathways are also affected, as shown by in vivo studies with serotonergic and glutamatergic radiotracers. The role played by the immune system during illness progression could be investigated with PET ligands that target the microglia/macrophage Translocator protein (TSPO) receptor. These agents have been used in PD patients and rodent models, although often without attempting correlations with other molecular or functional parameters. For example, neurodegeneration and brain plasticity can be monitored using the metabolic marker 2-Deoxy-2-[18F]fluoroglucose ([18F]-FDG), while oxidative stress can be probed using the copper-labeled diacetyl-bis(N-methyl-thiosemicarbazone) ([Cu]-ATSM) radioligand, whose striatal-specific binding ratio in PD patients seems to correlate with a disease rating scale and motor scores. Also, structural and functional modifications during disease progression may be evaluated by Magnetic Resonance Imaging (MRI), using different parameters as iron content or cerebral volume. In this review article, we propose an overview of in vivo clinical and non-clinical imaging research on neuroinflammation as an emerging marker of early PD. We also discuss how multimodal-imaging approaches could provide more insights into the role of the inflammatory process and related events in PD development.
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Project description:Parkinson's disease dementia is neuropathologically characterized by aggregates of α-synuclein (Lewy bodies) in limbic and neocortical areas of the brain with additional involvement of Alzheimer's disease-type pathology. Whilst immune activation is well-described in Parkinson's disease (PD), how it links to protein aggregation and its role in PD dementia has not been explored. We hypothesized that neuroinflammatory processes are a critical contributor to the pathology of PDD. To address this hypothesis, we examined 7 brain regions at postmortem from 17 PD patients with no dementia (PDND), 11 patients with PD dementia (PDD), and 14 age and sex-matched neurologically healthy controls. Digital quantification after immunohistochemical staining showed a significant increase in the severity of α-synuclein pathology in the hippocampus, entorhinal and occipitotemporal cortex of PDD compared to PDND cases. In contrast, there was no difference in either tau or amyloid-β pathology between the groups in any of the examined regions. Importantly, we found an increase in activated microglia in the amygdala of demented PD brains compared to controls which correlated significantly with the extent of α-synuclein pathology in this region. Significant infiltration of CD4+ T lymphocytes into the brain parenchyma was commonly observed in PDND and PDD cases compared to controls, in both the substantia nigra and the amygdala. Amongst PDND/PDD cases, CD4+ T cell counts in the amygdala correlated with activated microglia, α-synuclein and tau pathology. Upregulation of the pro-inflammatory cytokine interleukin 1β was also evident in the substantia nigra as well as the frontal cortex in PDND/PDD versus controls with a concomitant upregulation in Toll-like receptor 4 (TLR4) in these regions, as well as the amygdala. The evidence presented in this study show an increased immune response in limbic and cortical brain regions, including increased microglial activation, infiltration of T lymphocytes, upregulation of pro-inflammatory cytokines and TLR gene expression, which has not been previously reported in the postmortem PDD brain.
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Project description:Characterization of the key cellular targets contributing to sustained microglial activation in neurodegenerative diseases, including Parkinson's disease (PD), and optimal modulation of these targets can provide potential treatments to halt disease progression. Here, we demonstrated that microglial Kv1.3, a voltage-gated potassium channel, was transcriptionally upregulated in response to aggregated α-synuclein (αSynAgg) stimulation in primary microglial cultures and animal models of PD, as well as in postmortem human PD brains. Patch-clamp electrophysiological studies confirmed that the observed Kv1.3 upregulation translated to increased Kv1.3 channel activity. The kinase Fyn, a risk factor for PD, modulated transcriptional upregulation and posttranslational modification of microglial Kv1.3. Multiple state-of-the-art analyses, including Duolink proximity ligation assay imaging, revealed that Fyn directly bound to Kv1.3 and posttranslationally modified its channel activity. Furthermore, we demonstrated the functional relevance of Kv1.3 in augmenting the neuroinflammatory response by using Kv1.3-KO primary microglia and the Kv1.3-specific small-molecule inhibitor PAP-1, thus highlighting the importance of Kv1.3 in neuroinflammation. Administration of PAP-1 significantly inhibited neurodegeneration and neuroinflammation in multiple animal models of PD. Collectively, our results imply that Fyn-dependent regulation of Kv1.3 channels plays an obligatory role in accentuating the neuroinflammatory response in PD and identify Kv1.3 as a potential therapeutic target for PD.
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Project description:ObjectiveTo identify and validate causal protein targets that may serve as potential therapeutic interventions for both the onset and progression of Parkinson's disease (PD) through integrative proteomic and genetic analyses.MethodWe utilized large-scale plasma and brain protein quantitative trait loci (pQTL) datasets from the deCODE Health study and the Religious Orders Study/Rush Memory and Aging Project (ROS/MAP), respectively. Proteome-wide association studies (PWAS) were conducted using the OTTERS framework for plasma proteins and the FUSION tool for brain proteins, examining associations with PD onset and three progression phenotypes: composite, motor, and cognitive. Significant protein associations (FDR-corrected p < 0.05) from PWAS were further validated using summary-based Mendelian randomization (SMR), colocalization analyses, and reverse Mendelian randomization (MR) to establish causality. Phenome-wide Mendelian randomization (PheW-MR) was performed to assess potential side effects across 679 disease traits when targeting these proteins to reduce PD-related phenotype risk by 20%. Additionally, we conducted cellular distribution-based clustering using gene expression data from the Allen Brain Atlas (ABA) to explore the distribution of key proteins across brain regions, constructed protein-protein interaction (PPI) networks via the STRING database to explore interactions among proteins, and evaluated the druggability of identified targets using the DrugBank database to identify opportunities for drug repurposing.ResultOur analyses identified 25 candidate proteins associated with PD phenotypes, including 16 plasma proteins linked to PD progression (10 cognitive, 4 motor, and 3 composite) and 9 plasma proteins associated with PD onset. Notably, GPNMB was implicated in both plasma and brain tissues for PD onset. PheW-MR revealed predominantly beneficial side effects for the identified targets, with 83.7% of associations indicating positive outcomes and 16.3% indicating adverse effects. Cellular clustering categorized candidate targets into three distinct expression profiles across brain cell types using ABA. PPI network analysis highlighted one key interaction cluster among the proteins for PD cognitive progression and PD onset. Druggability assessment revealed 15 out of 25 proteins had repurposing opportunities for PD treatment.ConclusionWe have identified 25 causal protein targets associated with the onset and progression of PD, providing new insights into the research and development of treatment strategies for PD.
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Project description:The development of dementia is a devastating aspect of Parkinson's disease (PD), affecting nearly half of patients within 10 years post-diagnosis. For effective therapies to prevent and slow progression to PD dementia (PDD), the key mechanisms that determine why some people with PD develop early dementia, while others remain cognitively unaffected, need to be understood. Neuroinflammation and tau protein accumulation have been demonstrated in post-mortem PD brains, and in many other neurodegenerative disorders leading to dementia. However, whether these processes mediate dementia risk early on in the PD disease course is not established. To this end, we used PET neuroimaging with 11C-PK11195 to index neuroinflammation and 18F-AV-1451 for misfolded tau in early PD patients, stratified according to dementia risk in our 'Neuroinflammation and Tau Accumulation in Parkinson's Disease Dementia' (NET-PDD) study. The NET-PDD study longitudinally assesses newly-diagnosed PD patients in two subgroups at low and high dementia risk (stratified based on pentagon copying, semantic fluency, MAPT genotype), with comparison to age- and sex-matched controls. Non-displaceable binding potential (BPND) in 43 brain regions (Hammers' parcellation) was compared between groups (pairwise t-tests), and associations between BPND of the tracers tested (linear-mixed-effect models). We hypothesized that people with higher dementia risk have greater inflammation and/or tau accumulation in advance of significant cognitive decline. We found significantly elevated neuroinflammation (11C-PK11195 BPND) in multiple subcortical and restricted cortical regions in the high dementia risk group compared with controls, while in the low-risk group this was limited to two cortical areas. The high dementia risk group also showed significantly greater neuroinflammation than the low-risk group concentrated on subcortical and basal ganglia regions. Neuroinflammation in most of these regions was associated with worse cognitive performance (Addenbrooke's Cognitive Examination-III score). Overall neuroinflammation burden also correlated with serum levels of pro-inflammatory cytokines. In contrast, increases in 18F-AV-1451 (tau) BPND in PD versus controls were restricted to subcortical regions where off-target binding is typically seen, with no relationship to cognition found. Whole-brain 18F-AV-1451 burden correlated with serum phosphorylated tau181 levels. Although there was minimal regional tau accumulation in PD, regional neuroinflammation and tau burden correlated in PD participants, with the strongest association in the high dementia risk group, suggesting possible co-localization of these pathologies. In conclusion, our findings suggest that significant regional neuroinflammation in early PD might underpin higher risk for PDD development, indicating neuroinflammation as a putative early modifiable aetiopathological disease factor to prevent or slow dementia development using immunomodulatory strategies.
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Project description:Parkinson's disease (PD) is one of the most prevalent neurodegenerative aging disorders characterized by motor and non-motor symptoms due to the selective loss of midbrain dopaminergic (DA) neurons. The decreased viability of DA neurons slowly results in the appearance of motor symptoms such as rigidity, bradykinesia, resting tremor, and postural instability. These symptoms largely depend on DA nigrostriatal denervation. Pharmacological and surgical interventions are the main treatment for improving clinical symptoms, but it has not been possible to cure PD. Furthermore, the cause of neurodegeneration remains unclear. One of the possible neurodegeneration mechanisms is a chronic inflammation of the central nervous system, which is mediated by microglial cells. Impaired or dead DA neurons can directly lead to microglia activation, producing a large number of reactive oxygen species and pro-inflammatory cytokines. These cytotoxic factors contribute to the apoptosis and death of DA neurons, and the pathological process of neuroinflammation aggravates the primary morbid process and exacerbates ongoing neurodegeneration. Therefore, anti-inflammatory treatment exerts a robust neuroprotective effect in a mouse model of PD. Since discovering the first mutation in the α-synuclein gene (SNCA), which can cause disease-causing, PD has involved many genes and loci such as LRRK2, Parkin, SNCA, and PINK1. In this article, we summarize the critical descriptions of the genetic factors involved in PD's occurrence and development (such as LRRK2, SNCA, Parkin, PINK1, and inflammasome), and these factors play a crucial role in neuroinflammation. Regulation of these signaling pathways and molecular factors related to these genetic factors can vastly improve the neuroinflammation of PD.
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