Phenotypic manifestation of alpha-synuclein strains from Parkinson’s disease and multiple system atrophy in human dopaminergic neruons
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ABSTRACT:
PROVIDER: PRJNA629496 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11652312_1.fastq.gz | Fastqsanger.gz | |||
| SRR11652312_2.fastq.gz | Fastqsanger.gz | |||
| SRR11652313_1.fastq.gz | Fastqsanger.gz | |||
| SRR11652313_2.fastq.gz | Fastqsanger.gz | |||
| SRR11652314_1.fastq.gz | Fastqsanger.gz |
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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
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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.
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Project description:Phenotypic manifestation of alpha-synuclein strains derived from Parkinson’s disease and multiple system atrophy in human dopaminergic neurons
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Project description:Background: Pathological accumulation of aggregated α-synuclein (aSYN) is a common feature of Parkinson’s disease (PD). However, the mechanisms by which intracellular aSYN pathology contributes to dysfunction and degeneration of neurons in the brain are still unclear. A potentially relevant target of aSYN is the mitochondrion. To test this hypothesis, genetic and physiological methods were used to monitor mitochondrial function in substantia nigra pars compacta (SNc) dopaminergic and pedunculopontine nucleus (PPN) cholinergic neurons after stereotaxic injection of aSYN pre-formed fibrils (PFFs) into the mouse brain. Methods: aSYN PPFs were stereotaxically injected into the SNc or PPN of mice. Twelve weeks later, mice were studied using a combination of approaches, including immunocytochemical analysis, cell-type specific transcriptomic profiling, electron microscopy, electrophysiology and two-photon-laser-scanning microscopy of genetically encoded sensors for bioenergetic and redox status. Results: In addition to inducing a significant neuronal loss, SNc injection of PFFs induced the formation of intracellular, phosphorylated aSYN aggregates selectively in dopaminergic neurons. In these neurons, PFF-exposure decreased mitochondrial gene expression, reduced the number of mitochondria, increased oxidant stress, and profoundly disrupted mitochondrial adenosine triphosphate production. Consistent with an aSYN-induced bioenergetic deficit, the autonomous spiking of dopaminergic neurons slowed or stopped. PFFs also up-regulated lysosomal gene expression and increased lysosomal abundance, leading to the formation of Lewy-like inclusions. Similar changes were observed in PPN cholinergic neurons following aSYN PFF exposure. Conclusions: Taken together, our findings suggest that disruption of mitochondrial function is a proximal step in the cascade of events induced by aSYN pathology leading to dysfunction and degeneration of neurons at-risk in PD.
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Project description:Synuclein pathology disrupts mitochondrial function in dopaminergic and cholinergic neurons at-risk in Parkinson’s disease
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Project description:Parkinson’s disease (PD) is an age-related neurodegenerative disorder characterized by the degeneration of the nigrostriatal dopaminergic neurons, and by intraneuronal accumulation of aggregated α-synuclein (aSyn). Environmental factors contribute significantly to neurodegeneration in patients, and non-pharmacological interventions are increasingly explored. Among these, caloric restriction and time-restricted feeding have demonstrated beneficial effects in animal models of neurodegenerative diseases. The ketone body β-hydroxybutyrate (BHB) has been suggested to mediate some of these effects. In this study, we tested the therapeutic potential of intermittent fasting (IF, every other day feeding) in an aSyn-based mouse model of PD. IF was initiated four weeks after induction of aSyn pathology. Four weeks of IF mitigated the aSyn-induced degeneration of dopaminergic neurons and axon terminals. IF also reduced aSyn pathology as reported by staining for phosphorylated aSyn and Triton X-100 solubility. IF mitigated the aSyn-induced motor phenotype, the decrease in striatal dopamine and the decrease in synaptic markers. In transcriptomic analysis, we observed a robust modulation of genes involved in inflammation and microglia activation even with just brief IF treatment and without synuclein transduction. In primary mouse neurons, starvation and treatment with BHB were sufficient to induce autophagy and reduced αSyn pathology. Taken together, IF might constitute a plausible neuroprotective strategy for patients with Parkinson’s diseases. BHB-induced autophagy and altered neuroinflammation are pathways that potentially contribute to the protective effect.
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