Border-associated macrophages mediate the neuroinflammatory response in an alpha-synuclein model of Parkinson disease
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE178498 | GEO | 2021/06/20
REPOSITORIES: GEO
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Project description:Gastrointestinal (GI) dysfunction precedes motor symptoms in Parkinson disease (PD), implicating the enteric nervous system (ENS) in early disease pathogenesis. However, how the PD-associated protein alpha synuclein (alpha syn) contributes to ENS dysfunction, and whether this is influenced by inflammation, remains unresolved. Here, we show that tumor necrosis factor alpha (TNF alpha) increases alpha syn accumulation at mitochondria, disrupts the malate-aspartate shuttle (MAS), and induces a metabolic shift toward glutamine oxidation in iPSC derived enteric neural lineages (ENLs) from PD patients carrying alpha syn gene triplications. This metabolic rewiring leads to mitochondrial dysfunction, NAD+ depletion, and oxidative stress. Targeting glutamate metabolism with Chicago Sky Blue 6B restores mitochondrial function and reverses TNF alpha induced metabolic impairment. Combined transcriptomic and histological analyses of human gut tissue show that inflammation-associated MAS suppression and alpha syn upregulation are not confined to PD but are general hallmarks of intestinal inflammation. These findings highlight a conserved metabolic vulnerability in the ENS and establish iPSC ENLs as a powerful platform for modeling early inflammatory disease mechanisms.
2025-06-28 | MSV000098371 | MassIVE
Project description:Gastrointestinal (GI) dysfunction precedes motor symptoms in Parkinson disease (PD), implicating the enteric nervous system (ENS) in early disease pathogenesis. However, how the PD-associated protein alpha synuclein (alpha syn) contributes to ENS dysfunction, and whether this is influenced by inflammation, remains unresolved. Here, we show that tumor necrosis factor alpha (TNF alpha) increases alpha syn accumulation at mitochondria, disrupts the malate-aspartate shuttle (MAS), and induces a metabolic shift toward glutamine oxidation in iPSC derived enteric neural lineages (ENLs) from PD patients carrying alpha syn gene triplications. This metabolic rewiring leads to mitochondrial dysfunction, NAD+ depletion, and oxidative stress. Targeting glutamate metabolism with Chicago Sky Blue 6B restores mitochondrial function and reverses TNF alpha induced metabolic impairment. Combined transcriptomic and histological analyses of human gut tissue show that inflammation-associated MAS suppression and alpha syn upregulation are not confined to PD but are general hallmarks of intestinal inflammation. These findings highlight a conserved metabolic vulnerability in the ENS and establish iPSC ENLs as a powerful platform for modeling early inflammatory disease mechanisms.
2025-06-27 | MSV000098366 | MassIVE
Project description:Parkinson’s disease (PD) is a prevalent neurodegenerative disorder that is characterized by the selective loss of midbrain dopamine (DA)-producing neurons and the formation of α-synuclein (α-syn)-containing inclusions named Lewy bodies (LBs). Here, we report that the loss of glucocerebrosidase (GCase), coupled with α-syn overexpression, result in substantial accumulation of detergent-resistant α-syn aggregates and Lewy body-like inclusions (LBLIs) in human midbrain-like organoids (hMLOs). These LBLIs exhibit a highly similar structure to PD-associated LBs, by displaying a spherically symmetric morphology with an eosinophilic core, and containing α-syn and ubiquitin. Importantly, hMLOs generated from PD patient-derived inducible pluripotent stem cells (iPSCs) harboring SNCA triplication also exhibit subsequent degeneration of DA neurons and LBLI formation upon chronic GCase inhibitor treatment. Taken together, our hMLOs harbouring two major PD risk factors (GCase deficiency and overproduced α-syn) successfully recapitulate major pathophysiological signatures of the disease, and highlight the broad utility of brain organoid technology in modeling human neurodegenerative diseases.
2021-08-13 | E-MTAB-7302 | biostudies-arrayexpress
Project description:Parkinson’s disease (PD) is characterized by neuroinflammation, progressive loss of dopaminergic neurons, and accumulation of a-synuclein (a-Syn) into insoluble aggregates called Lewy pathology. The Line 61 a-Syn mouse is an established preclinical model of PD; Thy-1 is used to promote human a-Syn expression, and features of sporadic PD develop at 9-18 months of age. To accelerate the PD phenotypes, we injected sonicated human a-Syn preformed fibrils (PFFs) into the striatum, which produced phospho-Syn (p-a-Syn) inclusions in the substantia nigra pars compacta and significantly increased MHC Class II-positive immune cells. Additionally, there was enhanced infiltration and activation of innate and adaptive immune cells in the midbrain. We then used this new model, Line 61-PFF, to investigate the effect of inhibiting the JAK/STAT signaling pathway, which is critical for regulation of innate and adaptive immune responses. After administration of the JAK1/2 inhibitor AZD1480, immunofluorescence staining showed a significant decrease in p-a-Syn inclusions and MHC Class II expression. Flow cytometry showed reduced infiltration of CD4+ T-cells, CD8+ T-cells, CD19+ B-cells, dendritic cells, macrophages, and endogenous microglia into the midbrain. Importantly, single-cell RNA-Sequencing analysis of CD45+ cells from the midbrain identified 9 microglia clusters, 5 monocyte/macrophage (MM) clusters, and 5 T-cell (T) clusters, in which potentially pathogenic MM4 and T3 clusters were associated with neuroinflammatory responses in Line 61-PFF mice. AZD1480 treatment reduced cell numbers and cluster-specific expression of the antigen-presentation genes H2-Eb1, H2-Aa, H2-Ab1, and Cd74 in the MM4 cluster and proinflammatory genes such as Tnf, Il1b, C1qa, and C1qc in the T3 cluster. Together, these results indicate that inhibiting the JAK/STAT pathway suppresses the activation and infiltration of innate and adaptive cells, reducing neuroinflammation in the Line 61-PFF mouse model.
2024-05-31 | GSE264525 | GEO
Project description:Background: Cell-to-cell propagation of α-synuclein (α-syn) aggregates is thought to contribute to the pathogenesis of Parkinson’s disease (PD) and underlie the spread of α-syn neuropathology. Increased pro-inflammatory cytokine levels and activated microglia are present in PD and activated microglia can promote α-syn aggregation. However, it is unclear how microglia influence α-syn cell-to-cell transfer. Methods: We developed a clinically relevant mouse model to monitor α-syn prion-like propagation between cells; we transplanted wild-type mouse embryonic midbrain neurons into a mouse striatum overexpressing human α-syn (huα-syn) following adeno-associated viral injection into the substantia nigra. In this system, we depleted or activated microglial cells and determined the effects on the transfer of huα-syn from host nigrostriatal neurons into the implanted dopaminergic neurons, using the presence of huα-syn within the grafted cells as a readout. Results: First, we compared α-syn cell-to-cell transfer between host mice with a normal number of microglia to mice in which we had pharmacologically ablated 80% of the microglia from the grafted striatum. With fewer host microglia, we observed increased accumulation of huα-syn in grafted dopaminergic neurons. Second, we assessed the transfer of α-syn into grafted neurons in the context of microglia activated by one of two stimuli, lipopolysaccharide (LPS) or interleukin-4 (IL-4). LPS exposure led to a strong activation of microglial cells (as determined by microglia morphology and cytokine production) and significantly higher amounts of huα-syn in grafted neurons. In contrast, injection of IL-4 did not change the proportion of grafted dopamine neurons that contained huα-syn relative to controls. RNA sequencing analysis revealed differential gene expression between LPS and IL-4 injected mice; many genes were upregulated in LPS including those involved with the inflammatory response. Conclusions: The absence or the hyperstimulation of microglia affected α-syn transfer in the brain. Our results suggest that under resting, non-inflammatory conditions, microglia modulate the transfer of α-syn. Pharmacological regulation of neuroinflammation could represent a future avenue for limiting the spread of PD neuropathology.
2019-08-12 | GSE130683 | GEO
Project description:Kuznetsov2016(II) - α-syn aggregation
kinetics in Parkinson's
This theoretical model uses 2-step Finke-Watzky (FW) kinetics
todescribe the production, misfolding, aggregation, transport and
degradation of α-syn that may lead to Parkinson's Disease
(PD). Deregulated α-syn degradation is predicted to be
crucialfor PD pathogenesis.
This model is described in the article:
What can trigger the onset
of Parkinson's disease - A modeling study based on a
compartmental model of α-synuclein transport and aggregation in
neurons.
Kuznetsov IA, Kuznetsov AV.
Math Biosci 2016 Aug; 278: 22-29
Abstract:
The aim of this paper is to develop a minimal model
describing events leading to the onset of Parkinson's disease
(PD). The model accounts for α-synuclein (α-syn) production in
the soma, transport toward the synapse, misfolding, and
aggregation. The production and aggregation of polymeric α-syn
is simulated using a minimalistic 2-step Finke-Watzky model. We
utilized the developed model to analyze what changes in a
healthy neuron are likely to lead to the onset of α-syn
aggregation. We checked the effects of interruption of α-syn
transport toward the synapse, entry of misfolded (infectious)
α-syn into the somatic and synaptic compartments, increasing
the rate of α-syn synthesis in the soma, and failure of α-syn
degradation machinery. Our model suggests that failure of α-syn
degradation machinery is probably the most likely cause for the
onset of α-syn aggregation leading to PD.
This model is hosted on
BioModels Database
and identified by:
BIOMD0000000615.
To cite BioModels Database, please use:
BioModels Database:
An enhanced, curated and annotated resource for published
quantitative kinetic models.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to
the public domain worldwide. Please refer to
CC0
Public Domain Dedication for more information.
2024-09-02 | BIOMD0000000615 | BioModels
Project description:Dissect the transcriptional consequences of neuroinflammation and the role of the kinase LRRK2 in regulating neuronal responses in human induced pluripotent stem cell (hiPSC)-derived neurons exposed to pro-inflammatory conditions relevant to Parkinson’s disease (PD) and Alzheimer’s disease (AD).Dopaminergic neurons (PD context) and cholinergic neurons (AD context) were differentiated from hiPSCs and subsequently cultured in glial-conditioned medium containing either α-synuclein pre-formed fibrils (α-syn pffs) or amyloid-β (Aβ) fibrils, for PD and aAD respectively. Neuronal cultures were exposed to inflammed media to model chronic inflammatory stress.
2025-10-02 | GSE308143 | GEO
Project description:Alpha-synuclein (α-syn) aggregation and immune activation represent hallmark pathological events in Parkinson’s disease (PD). The PD-associated immune response encompasses both brain and peripheral immune cells, although little is known about the immune proteins relevant for such response. We propose that the upregulation of CD163 observed in blood monocytes and in the responsive microglia in the PD patients is a protective mechanism in the disease. To investigate this, we used the PD model based on intrastriatal injections of murine α-syn pre-formed fibrils (PFF) in CD163 knockout (KO) mice and wild-type littermates. CD163KO females revealed an impaired and differential early immune response to α-syn pathology as revealed by immunohistochemical and transcriptomic analysis. After 6 months, CD163KO females showed an exacerbated immune response and α-syn pathology, which ultimately led to a dopaminergic neurodegeneration of greater magnitude. These findings support a novel, sex-dimorphic neuroprotective role for CD163 during α-syn-induced neurodegeneration.
2023-12-14 | GSE243536 | GEO
Project description:LC-MS/MS analyses were performed on soluble alpha-Syn purified from PD and various alpha-Synucleinopathies to systematically explore the landscape of post-translational modifications (PTMs) on soluble alpha-Syn, leading to the identification of a large number of novel alpha-Syn PTMs.
2022-10-30 | MSV000090618 | MassIVE
Project description:Parkinson's disease is the second most common neurodegenerative disorder, whose characteristic pathology involves progressive loss of dopaminergic neurons and formation of Lewy bodies(LBs) in the substantia nigra(SN). Aggregated and misfolded α-synuclein(α-syn) is the major constituent of LBs. As the newly discovered pathway of renin-angiotensin system (RAS), Angiotensin-(1-7)(Ang-(1-7)) and its receptor Mas have attracted increasing attentions for their correlation with PD progression, but underlying mechanisms remain not very clear. Based on the above, this study established PD models of mice and primary dopaminergic neurons with overexpression of α-syn, then discussed the effect of Ang-(1-7)/Mas on these models combined with downstream lncRNA and miRNA. The findings show that Ang-(1-7) alleviates behavioral disorders, rescues dopaminergic neurons loss and lowers α-syn expression in the SN of hα-syn(A53T) overexpressed PD mice. We also discover that Ang-(1-7) decreases the level of α-syn and apoptosis in the hα-syn(A53T) overexpressed dopaminergic neurons through NEAT1/miR-153-3p axis. Moreover, miR-153-3p expression in peripheral blood is found negatively correlated with that of α-syn. These results not only uncovered the significance and related mechanisms of Ang-(1-7)/Mas on α-syn pathology, but also throwed a new light upon miR-153-3p and NEAT1 as biomarkers and therapeutic targets in PD.
2025-01-15 | GSE248268 | GEO