TNFα-NF-κB activation through pathological α-Synuclein disrupts the BBB and exacerbates axonopathy
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE298722 | GEO | 2025/06/07
REPOSITORIES: GEO
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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:Alpha-Synuclein (α-Syn) association with exosomes has been extensively studied both as a physiological process but also as a means of disease transmission under pathological conditions, via an elusive mechanism. Here, we utilized the preformed fibril (PFF) mouse model, as a source of brain-derived exosomes and assessed their pathogenic capacity following intrastriatal injections in host wild type (WT) mouse brain. We further investigated the impact of PFF toxic stimulus in the exosomal cargo independent of the endogenous α-Syn, by isolating exosomes from PFF-injected α-Syn knockout mice. We found that PFF inoculation does not alter the morphology, size distribution, and quantity of brain-derived exosomes, however we show, for the first time, that it triggers changes in the exosomal protein cargo related to synaptic and mitochondrial function, as well as metabolic processes. Importantly, we showed that the presence of the endogenous α-Syn is essential for the exosomes to acquire a pathogenic identity/status, allowing them to mediate disease transmission by inducing phospho-α-Syn pathology, astrogliosis and synaptic alterations in the host mouse brain, thus supporting a role of exosomes in a prion-like mode of infection.
2023-08-04 | PXD036301 | Pride
Project description:Brain aggregates of α-synuclein (α-syn) characterizes a group of diseases defined as synucleinopathies. Recent studies implicate neuroinflammation as one of the central pathogenic mechanisms. However, how inflammation is linked to the α-syn pathology is still unknown. We wanted to address this by a ‘double-hit’ approach. Three weeks after intra-striatal injections of human α-syn pre-formed fibrils (PFF), mice were subjected for 3 weeks to repeated intraperitoneal injections of low concentrations (1 mg/ml) of lipopolysaccharide (LPS), a component of gram-negative bacteria. Histological analysis confirmed brain propagation of α-syn aggregation in PFF-injected mice independent of LPS-injections. No motor dysfunction was observed at this stage as measured in the pole test. Spleen immune cell profiling and multiplex cytokine analysis confirmed LPS-induced changes in T- and B-cells populations, monocytes, and neutrophils, and increased brain TNF-α, IL-β, IL-10 and KC/GRO levels. LC-MS/MS analysis in the forebrain area and subsequent downstream ReactomeGSA pathway analysis revealed that PFF-injections induced alterations in mitochondrial metabolism and neurotransmitter signaling. Systemic inflammation resulted in an overrepresentation of complement and coagulation pathways and upregulation of integrin and B cell receptor signaling in the PFF-injected mice.
2024-09-05 | PXD039193 | Pride
Project description:Examination of early phases of synucleinopathy when inclusions are present, but long before neurodegeneration occurs, is critical to both understanding disease progression and the development of disease modifying therapies. The rat alpha-synuclein (α-syn) preformed fibril (PFF) model induces synchronized synucleinopathy that recapitulates the pathological features of Parkinson’s disease (PD) and can be used to study synucleinopathy progression. In this model, phosphorylated α-syn (pSyn) inclusion-containing neurons and reactive microglia (major histocompatibility complex-II immunoreactive) peak in the substantia nigra pars compacta (SNpc) months before appreciable neurodegeneration. However, it remains unclear which specific genes are driving these phenotypic changes. To identify transcriptional changes associated with early synucleinopathy, we used laser capture microdissection of the SNpc paired with RNA sequencing (RNASeq). Precision collection of the SNpc allowed for the assessment of differential transcript expression in the nigral dopamine neurons and proximal glia. Transcripts upregulated in early synucleinopathy were mainly associated with an immune response, whereas transcripts downregulated were associated with neurotransmission and the dopamine pathway. A subset of 29 transcripts associated with neurotransmission/vesicular release and the dopamine pathway were verified in a separate cohort of males and females to confirm reproducibility. Within this subset, fluorescent in situ hybridization (FISH) was used to localize decreases in the Syt1 and Slc6a3 transcripts to pSyn inclusion-containing neurons. Identification of transcriptional changes in early synucleinopathy provides insight into the molecular mechanisms driving neurodegeneration.
2023-10-24 | GSE246112 | GEO
Project description:Aggregated α-synuclein (α-SYN) proteins, encoded by the SNCA gene, are hallmarks of Lewy body disease (LBD), affecting multiple brain regions. However, the specific mechanisms underlying α-SYN pathology in cortical neurons, crucial for LBD-associated dementia, remain unclear. Here, we generated human cortical LBD models by differentiating induced pluripotent stem cells (iPSCs) from SNCA triplication LBD patients into cerebral organoids and observed increased levels of pathological α-SYN in these organoids. Single-cell RNA sequencing revealed prominent expression of the SNCA gene in excitatory neurons, which exhibited synaptic and mitochondrial dysfunction, consistent with findings in the cortex of LBD human brains. Furthermore, screening 1280 FDA-approved drugs identified four candidates, which inhibited α-SYN seeding in RT-QuIC assay, reduced α-SYN aggregation and alleviated mitochondrial dysfunction in SNCA triplication iPSC models. Our findings provide valuable insights into the development of cortical LBD models and the discovery of potential drugs targeting α-SYN aggregation.
2024-09-18 | GSE236002 | GEO
Project description:Aggregated α-synuclein (α-SYN) proteins, encoded by the SNCA gene, are hallmarks of Lewy body disease (LBD), affecting multiple brain regions. However, the specific mechanisms underlying α-SYN pathology in cortical neurons, crucial for LBD-associated dementia, remain unclear. Here, we generated human cortical LBD models by differentiating induced pluripotent stem cells (iPSCs) from SNCA triplication LBD patients into cerebral organoids and observed increased levels of pathological α-SYN in these organoids. Single-cell RNA sequencing revealed prominent expression of the SNCA gene in excitatory neurons, which exhibited synaptic and mitochondrial dysfunction, consistent with findings in the cortex of LBD human brains. Furthermore, screening 1280 FDA-approved drugs identified four candidates, which inhibited α-SYN seeding in RT-QuIC assay, reduced α-SYN aggregation and alleviated mitochondrial dysfunction in SNCA triplication iPSC models. Our findings provide valuable insights into the development of cortical LBD models and the discovery of potential drugs targeting α-SYN aggregation.
2024-09-18 | GSE235914 | GEO
Project description:Synucleinopathies are triggered by the aggregation of α-synuclein (αSyn), leading to progressive neurodegeneration. However, the intracellular mechanism of αSyn aggregation remains unclear. Here we show that assembly of RNA G-quadruplexes (rG4s) form scaffolds for αSyn aggregation, contributing to neurodegeneration. Purified αSyn binds rG4s directly through the N-terminus. rG4 itself undergoes phase separation and assembly by Ca2+, accelerating the sol-gel phase transition of αSyn. In αSyn preformed fibrils (PFF)-treated neurons, rG4s assembly composed of synaptic mRNAs co-aggregates with αSyn upon Ca2+ excess influx into cytoplasm, eliciting synaptic dysfunction. Artificial assembly of rG4s using an optogenetic approach evokes αSyn aggregation and neuronal dysfunction. Administration of 5-aminolevulinic acid (5-ALA), a prodrug of protoporphyrin IX (PpIX) that prevents phase separation of rG4s, attenuating αSyn aggregation, neurodegeneration, and progressive motor deficits in PFF-injected synucleinopathy mice. Together, assembly of rG4s due to dysregulation of intracellular Ca2+ homeostasis accelerates αSyn phase transition and aggregation may contribute to pathogenesis of synucleinopathies.
2023-07-18 | GSE234238 | 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:Parkinson’s disease (PD) is a neurodegenerative disorder characterized by a loss of dopaminergic neurons. Recent studies suggested the association of zinc finger protein 184 (ZNF184) with PD. However, the functional role of ZNF184 in PD pathogenesis remains unclear. Therefore, we aimed to confirm this association and the effects of ZNF184 in a mouse model of PD and human patients with PD.We found that ZNF184 levels were decreased in the substantia nigra (SN) of α-synuclein preformed fibril (α-syn PFF)-injected mice and cells treated with PD toxins. Furthermore, ZNF184 was reduced in the cortex and SN of patients with PD, suggesting an association between ZNF184 and PD pathogenesis. In ZNF184-overexpressing cells, RNA-sequencing analysis revealed significant alterations in several protein-coding genes including interleukin enhancer binding factor 3 (ILF3). Bioinformatic analysis identified potential ZNF184 binding motifs within the ILF3 promoter, and ZNF184 occupancy was confirmed. Since ILF3 inhibits the biogenesis of microRNA-7 (miR-7), which regulates α-synuclein aggregation, we administered the miR-7 inducer, scutellarin to α-syn PFF-injected mice, preventing dopaminergic neuron and reinstating motor abilities. Our findings suggest that ZNF184 promotes miR-7 upregulation by suppressing ILF3 transcription, revealing a novel pathway that could serve as a promising therapeutic target for the treatment of PD.
2024-11-20 | GSE282345 | GEO
Project description:Parkinson’s disease (PD) is a neurodegenerative disease characterized by progressive motor symptoms and alpha-synuclein (αsyn) aggregation in the nervous system. For unclear reasons, PD patients with certain GBA mutations (GBA-PD) have a more aggressive clinical progression. Two testable hypotheses that can potentially account for this phenomenon are that GBA1 mutations promote αsyn spread or drive the generation of highly pathogenic αsyn polymorphs (i.e., strains). We tested these hypotheses by treating homozygous GBA1 D409V knockin (KI) mice with human α-syn-preformed fibrils (PFFs) and treating wild-type mice (WT) with several αsyn-PFF polymorphs amplified from brain autopsy samples collected from patients with idiopathic PD and GBA-PD patients with either homozygous or heterozygous GBA1 mutations. Robust phosphorylated-αsyn (PSER129) positive pathology was observed at the injection site (i.e., the olfactory bulb granular layer) and throughout the brain six months following PFF injection. The PFF seeding efficiency and degree of spread were similar regardless of the mouse genotype or PFF polymorphs. We found that PFFs amplified from the human brain, regardless of patient genotype, were generally more effective seeders than wholly synthetic PFFs (i.e., non-amplified); however, PFF concentration differed between these two studies, and this might also account for the observed differences. To investigate whether the molecular composition of pathology differed between different seeding conditions, we permed Biotinylation by Antibody Recognition on PSER129 (BAR-PSER129). We found that for BAR-PSER129, the endogenous PSER129 pool dominated identified interactions, and thus, very few potential interactions were explicitly identified for seeded pathology. However, we found Dctn2 interaction was shared across all PFF conditions, and Nckap1 and Ap3b2 were unique to PFFs amplified from GBA-PD brains of heterozygous mutation carriers. In conclusion, both the genotype and αsyn strain had little effect on overall seeding efficacy and global PSER129-interactions.
2024-02-22 | PXD045437 | Pride