GPNMB confers risk for Parkinson’s disease through interaction with alpha-synuclein
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA850079 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR19720419.fastq.gz | Fastqsanger.gz | |||
| SRR19720420.fastq.gz | Fastqsanger.gz | |||
| SRR19720421.fastq.gz | Fastqsanger.gz | |||
| SRR19720422.fastq.gz | Fastqsanger.gz | |||
| SRR19720423.fastq.gz | Fastqsanger.gz |
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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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Project description:Abnormal accumulation of aggregated proteins and sustained microglial activation are important contributors of neurodegenerative process in neurological diseases. Recent studies have shown that aggregation-prone proteins, such as a-synuclein, the protein implicated in Parkinson’s disease (PD), are released from neuronal cells and thus present in the extracellular fluid, pointing to the possible paracrine effects of these proteins on microglial immune responses. However, the mechanism underlying the disease-associated microglial activation and the role of neuronal proteins in this process remain unknown. Here, we show that extracellular a-synuclein released from neuronal cells is an endogenous ligand of toll-like receptor 2 (TLR2) and activates microglia, which in turn induces neurodegeneration. Interaction between neuron-released a-synuclein and TLR2 and subsequent activation of the TLR2 signaling were demonstrated comprehensively by using computational modeling of signaling network and by the experimental validation in TLR2-deficient microglia both in vitro and in vivo. In contrast to the neuron-released a-synuclein, recombinant a-synuclein proteins, including monomer, oligomer, fibril, or nitrated forms, were not able to interact or activate TLR2, suggesting that neuronal cells have a mechanism of enriching specific forms of a-synuclein capable of activating TLR2 during the process of releasing this protein. Taken together, the results suggest that both neuron-released extracellular a-synuclein and TLR2 might be novel therapeutic targets for modifying neuroinflammation in PD and related neurodegenerative diseases. We collected culture media from differentiated SH-SY5Y cells overexpressing either human a-synuclein (alpha-SCM) or beta-galactosidase (LZCM) and treat these media to primary rat microglia at the concentration of a-synuclein of 1.1M. Transcriptome analyses with microglial cells treated with either aSCM or LZCM at two different time points, 6 h and 24 h.
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