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: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: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: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
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:Althougha-synuclein is implicated in the pathogenesis of Parkinson’s disease and related disorders, it remains unclear whether specific conformations or levels ofa-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 a-synuclein was imprinted into synthetic or disease-relevant conformations. We used a-synuclein fibrils generated de novo or amplified from homogenates of brains affected with Parkinson’s disease (n=3) or multiple system atrophy (n=5). We found that a 2.5-fold increase in a-synuclein levels in a-synuclein gene triplication neurons promoted seeded aggregation in a dose and time-dependent fashion, which was associated with a further increase in a-synuclein gene expression. Progressive neuronal loss was observed only in a-synuclein triplication neurons seeded with brain-amplified fibrils. Transcriptomic analysis and isogenic correction of a-synuclein triplication revealed that intraneuronalalpha-synuclein levels solely and sufficiently explained vulnerability to neuronal death
2021-04-13 | GSE171999 | 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: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:The etiology of Parkinson’s disease (PD) remains elusive, and the limited availability of suitable animal models hampers research on pathogenesis and drug development. We report the development of a cynomolgus monkey model of PD that combines AAV-mediated overexpression of α-synuclein into the substantia nigra with injection of Poly(ADP-ribose) (PAR) into the striatum. Our results show that pathological processes were accelerated, including dopaminergic neuron degeneration, Lewy Bodies aggregation, and hallmarks of inflammation in microglia and astrocytes. Behavioral phenotypes, dopamine transporter imaging and transcriptomic profiling further demonstrate consistencies between the model and PD patients. This model can help to determine mechanisms underlying PD impacted by α-synuclein and PAR and aid in accelerated development of therapeutic strategies for PD.
2024-09-20 | GSE276753 | GEO
Project description:Although-synuclein is implicated in the pathogenesis of Parkinson’s disease and related disorders, it remains unclear whether specific conformations or levels of-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 -synuclein triplication or controls where endogenous -synuclein was imprinted into synthetic or disease-relevant conformations. We used -synuclein fibrils generated de novo or amplified from homogenates of brains affected with Parkinson’s disease (n=3) or multiple system atrophy (n=5). We found that a 2.5-fold increase in -synuclein levels in -synuclein gene triplication neurons promoted seeded aggregation in a dose and time-dependent fashion, which was associated with a further increase in -synuclein gene expression. Progressive neuronal loss was observed only in -synuclein triplication neurons seeded with brain-amplified fibrils. Transcriptomic analysis and isogenic correction of -synuclein triplication revealed that intraneuronal-synuclein levels solely and sufficiently explained vulnerability to neuronal death. Proximity-dependent biotinylation in living cells identified 56 differentially interacting proteins with endogenously assembled -synuclein including evasion of Parkinson’s disease-associated deglycase DJ-1 by aggregates triggered with brain amplified fibrils. Knockout of DJ-1 and related glyoxalase-1 in cell lines increased -synuclein aggregation. Similarly, methylglyoxal treatment or CRISPR/Cas9 knockout of DJ-1 in iPSC-derived dopaminergic neurons enhanced fibril-induced aggregation and cell death. Thus, toxicity of -synuclein strains depends on aggregate burden, which is determined by monomer levels and conformation which dictates differential interactomes. Our results define parameters for iPSC-based modellingof -synuclein pathology using brain amplified fibrils and demonstrate how Parkinson’s disease-associated genes influence the phenotypic manifestation of strains in human neurons.
2021-04-19 | PXD024198 | Pride