Neurodegeneration and Neuroinflammation are Linked, but Independent of α-Synuclein Inclusions, in a Seeding/Spreading Mouse Model of Parkinson’s Disease
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PROVIDER: PRJNA655395 | ENA |
REPOSITORIES: ENA
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Project description:A key process of neurodegeneration in Parkinson's disease (PD) is the transneuronal spreading of alpha-synuclein. Alpha-synuclein is a presynaptic protein that is implicated in the pathogenesis of PD and other synucleinopathies, where it forms, upon intracellular aggregation, pathological inclusions. Other hallmarks of PD include neurodegeneration and microgliosis in susceptible brain regions. Whether it is primarily transneuronal spreading of a-synuclein particles, inclusion formation, or other mechanisms, such as inflammation, that cause neurodegeneration in PD is unclear. We used spreading/aggregation of alpha-synuclein induced by intracerebral injection of a-synuclein preformed fibrils into the mouse brain to address this question. We performed quantitative histological analysis for a-synuclein inclusions, neurodegeneration, and microgliosis in different brain regions, and a gene expression profiling of the ventral midbrain, at two different timepoints after disease induction. We observed significant neurodegeneration and microgliosis in brain regions not only with, but also withouta-synuclein inclusions. We also observed prominent microgliosis in injured brain regions that did not correlate with neurodegeneration nor with inclusion load. In longitudinal gene expression profiling experiments, we observed early and unique alterations linked to microglial mediated inflammation that preceded neurodegeneration, indicating an active role of microglia in inducing neurodegeneration. Our observations indicate that a-synuclein inclusion formation is not the major driver in the early phases of PD-like neurodegeneration, but that diffusible, oligomeric a-synuclein species, which induce unusual microglial reactivity, play a key role in this process.
2020-11-02 | GSE155716 | GEO
Project description:A key pathological process in Parkinson's disease (PD) is the transneuronal spreading of α-synuclein. Alpha-synuclein (α-syn) is a presynaptic protein that, in PD, forms pathological inclusions. Other hallmarks of PD include neurodegeneration and microgliosis in susceptible brain regions. Whether it is primarily transneuronal spreading of α-syn particles, inclusion formation, or other mechanisms, such as inflammation, that cause neurodegeneration in PD is unclear. We used a model of spreading of α-syn induced by striatal injection of α-syn preformed fibrils into the mouse striatum to address this question. We performed quantitative analysis for α-syn inclusions, neurodegeneration, and microgliosis in different brain regions, and generated gene expression profiles of the ventral midbrain, at two different timepoints after disease induction. We observed significant neurodegeneration and microgliosis in brain regions not only with, but also without α-syn inclusions. We also observed prominent microgliosis in injured brain regions that did not correlate with neurodegeneration nor with inclusion load. Using longitudinal gene expression profiling, we observed early gene expression changes, linked to neuroinflammation, that preceded neurodegeneration, indicating an active role of microglia in this process. Altered gene pathways overlapped with those typical of PD. Our observations indicate that α-syn inclusion formation is not the major driver in the early phases of PD-like neurodegeneration, but that microglia, activated by diffusible, oligomeric α-syn, may play a key role in this process. Our findings uncover new features of α-syn induced pathologies, in particular microgliosis, and point to the necessity for a broader view of the process of α-syn spreading.
| S-EPMC9305192 | biostudies-literature
Project description:Parkinson’s disease (PD) is characterized by the accumulation of misfolded and aggregated alpha-synuclein (α-syn) into intraneuronal inclusions named Lewy bodies (LB). Although it is widely believed that α-syn plays a central role in the pathogenesis of PD, the processes that govern α-syn fibrillization and LB formation remain poorly understood. In this work, we sought to dissect the spatiotemporal events involved in the biogenesis of the LBs at the genetic, molecular, biochemical, structural, and cellular levels. Towards this goal, we further developed a seeding-based model of α-syn fibrillization to generate a neuronal model that reproduces all the key events leading to LB formation; including seeding, fibrillization, and the formation of inclusions that recapitulate many of the biochemical, structural, and organizational features of bona fide LBs. Using an integrative omics, biochemical and imaging approach, we dissected the molecular events associated with the different stages of LB formation and their contribution to neuronal dysfunction and degeneration. In addition, we demonstrate that LB formation involves a complex interplay between α-syn fibrillization, post-translational modifications, and interactions between α-syn aggregates and membranous organelles, including mitochondria, the autophagosome and endolysosome. Finally, we show that the process of LB formation, rather than simply fibril formation, is the major driver of neurodegeneration through disruption of cellular functions and inducing mitochondria damage and deficits, and synaptic dysfunctions. We believe that this model represents a powerful platform to further investigate the mechanisms of LB formation and clearance and to screen and evaluate novel therapeutics targeting α-syn aggregation and LB formation.
2020-01-15 | GSE142416 | GEO
Project description:Abnormal neuronal aggregation of a-synuclein is implicated in the development of Parkinson’s disease. Glial cells also show extensive a-synuclein pathology and are thought to contribute to disease progression. However, the mechanism that produces the glial a-synuclein pathology and the interaction between neurons and glia in the disease-inflicted microenvironment remain unknown. Here, we show that in neuronal cells misfolded a-synuclein proteins are selectively translocated into vesicles, leading to exocytosis of the aggregated forms. More importantly, our data demonstrate that astrocytes take up the neuron-derived a-synuclein aggregates and produce a-synuclein inclusions similar to the ones found in human brains. This uptake is paralleled by changes in the gene expression profile reflecting an inflammatory response. These results suggest that astroglial a-synuclein pathology is produced by cell-to-cell transmission of neuronal a-synuclein aggregates. This transmission step is thus an important mediator of pathogenic glial responses and could qualify as a new therapeutic target. To determine how astrocytes respond to extracellular a-synuclein, gene expression profiles were established and analyzed for nearly 22,000 rat genes using the Illumina RatRef-12 Expression BeadChip. Total RNA was isolated from astrocytes exposed for 6h or 24h to conditioned medium from cultures of a-synuclein or lacZ expressing cells.
2010-01-11 | E-GEOD-11574 | biostudies-arrayexpress
Project description:Abnormal neuronal aggregation of a-synuclein is implicated in the development of Parkinson’s disease. Glial cells also show extensive a-synuclein pathology and are thought to contribute to disease progression. However, the mechanism that produces the glial a-synuclein pathology and the interaction between neurons and glia in the disease-inflicted microenvironment remain unknown. Here, we show that in neuronal cells misfolded a-synuclein proteins are selectively translocated into vesicles, leading to exocytosis of the aggregated forms. More importantly, our data demonstrate that astrocytes take up the neuron-derived a-synuclein aggregates and produce a-synuclein inclusions similar to the ones found in human brains. This uptake is paralleled by changes in the gene expression profile reflecting an inflammatory response. These results suggest that astroglial a-synuclein pathology is produced by cell-to-cell transmission of neuronal a-synuclein aggregates. This transmission step is thus an important mediator of pathogenic glial responses and could qualify as a new therapeutic target.
2010-01-12 | GSE11574 | GEO
Project description:Aggregated alpha-synuclein (α-syn) is a principal constituent of Lewy bodies (LBs) and glial cytoplasmic inclusions (GCIs) that are observed respectively inside neurons in Parkinson’s disease (PD) and oligodendrocytes in multiple system atrophy (MSA). Yet, the cellular origin, the exact pathophysiological role, and the mechanism of formation of these inclusions remain to be elucidated. It has recently been proposed that pathological α-syn inclusions are capable of eventually causing the demise of the host cell by virtue of the cumulative sequestration of partner proteins and organelles. In particular, the hypothesis of a local cross-seeding of other fibrillization-prone proteins like tau or TDP-43 has also been put forward. The objective of this study was to examine the composition of these inclusions to gain insight into their origin and mechanisms of formation. We submitted sarkosyl-insoluble extracts of post-mortem brain tissue from PD and MSA patients and control subjects to a comparative proteomic analysis to address these points.
2022-02-17 | PXD024998 | Pride
Project description:Activation of microglia is a prominent pathological feature in tauopathies, including Alzheimer’s disease. How microglia activation contributes to tau toxicity remains largely unknown. Here we show that nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling, activated by tau, drives microglial-mediated tau propagation and toxicity. Constitutive activation of microglial NF-κB exacerbated, while inactivation diminished, tau seeding and spreading in young PS19 mice. Inhibition of NF-B activation enhanced the retention while reduced the release of internalized pathogenic tau fibrils from primary microglia and rescued microglial autophagy deficits. Remarkably, inhibition of microglial NF-κB in aged PS19 mice rescued tau-mediated learning and memory deficits, restored overall transcriptomic changes while increasing neuronal tau inclusions. Single cell RNA-seq revealed that tau-associated disease states in microglia were diminished by NF-B inactivation and further transformed by constitutive NF-B activation. Our study establishes a central role for microglial NF-B signaling in mediating tau spreading and toxicity in tauopathy.
2022-03-10 | GSE198014 | GEO
Project description:Activation of microglia is a prominent pathological feature in tauopathies, including Alzheimer’s disease. How microglia activation contributes to tau toxicity remains largely unknown. Here we show that nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling, activated by tau, drives microglial-mediated tau propagation and toxicity. Constitutive activation of microglial NF-κB exacerbated, while inactivation diminished, tau seeding and spreading in young PS19 mice. Inhibition of NF-B activation enhanced the retention while reduced the release of internalized pathogenic tau fibrils from primary microglia and rescued microglial autophagy deficits. Remarkably, inhibition of microglial NF-κB in aged PS19 mice rescued tau-mediated learning and memory deficits, restored overall transcriptomic changes while increasing neuronal tau inclusions. Single cell RNA-seq revealed that tau-associated disease states in microglia were diminished by NF-B inactivation and further transformed by constitutive NF-B activation. Our study establishes a central role for microglial NF-B signaling in mediating tau spreading and toxicity in tauopathy.
2022-03-10 | GSE198013 | GEO
Project description:Aggregated alpha-synuclein (α-syn) is a principal constituent of Lewy bodies (LBs) and glial cytoplasmic inclusions (GCIs) that are observed respectively inside neurons in Parkinson’s disease (PD) and oligodendrocytes in multiple system atrophy (MSA). Yet, the cellular origin, the exact pathophysiological role, and the mechanism of formation of these inclusions remain to be elucidated. It has recently been proposed that pathological α-syn inclusions are capable of eventually causing the demise of the host cell by virtue of the cumulative sequestration of partner proteins and organelles. In particular, the hypothesis of a local cross-seeding of other fibrillization-prone proteins like tau or TDP-43 has also been put forward. The objective of this study was to examine the composition of these inclusions to gain insight into their origin and mechanisms of formation. We submitted total solubilized and sarkosyl-insoluble extracts of post-mortem brain tissue from PD and MSA patients and control subjects to a comparative proteomic analysis to address these points. In parallel, we used proteomics for α-syn quantification in total solubilized brain homogenates and the respective sarkosyl-insoluble pellets as an unbiased validation of our results obtained by immunoblotting of these samples and fractions.
2024-03-25 | PXD039575 | Pride
Project description:Although α-synucleinis implicated in the pathogenesis of Parkinson’s disease and related disorders, it remains unclear whether specific conformations or levels of α-synuclein assemblies are toxic and how they cause progressive loss of human dopaminergic neurons. To address this issue, we used iPSC-derived dopaminergic neurons with a-synuclein triplication or controls where endogenous α-synuclein was imprinted into synthetic or disease-relevant conformations. We used α-synuclein fibrils generated de novo or amplified from homogenates of brains affected with Parkinson’s disease (n=3) .We found that a 2.5-fold increase in α-synuclein levels in α-synuclein gene triplication neurons promoted seeded aggregation in a dose and time-dependent fashion, which was associated with a further increase in α-synuclein gene expression.Transcriptomic analysis and isogenic correction of α-synuclein triplication revealed that intraneuronal α-synuclein levels solely and sufficiently explained vulnerability to cell death.
2020-09-02 | GSE149632 | GEO