Abstract
Backgroundα-Synuclein is a presynaptic protein abundant in the cytoplasmic compartment of neurons, whereas its presence in the extracellular space has also been observed under physiological conditions. Extracellular α-synuclein has pathological significance, exhibiting cellular toxicity and impairment of synaptic transmission. Notably, misfolded α-synuclein drives the cell-to-cell propagation of pathology via the extracellular space. However, the primary mechanism that regulates the extracellular levels of α-synuclein remains to be determined.MethodsUsing several mechanistically distinct methods to modulate neuronal/synaptic activities in primary neuronal culture and in vivo microdialysis, we examined the involvement of neuronal/synaptic activities on α-synuclein release.ResultsWe demonstrate here that physiological release of endogenous α-synuclein highly depends on intrinsic neuronal activities. Elevating neuronal activity rapidly increased, while blocking activity decreased, α-synuclein release. In vivo microdialysis experiments in freely moving mice revealed that ~ 70% of extracellular α-synuclein arises from neuronal activity-dependent pathway. Selective modulation of glutamatergic neurotransmission altered extracellular α-synuclein levels, implicating this specific neuronal network in the mechanism of activity-dependent release of α-synuclein. While neuronal activity tightly regulated α-synuclein release, elevated synaptic vesicle exocytosis per se was capable to elicit α-synuclein release. We also found that extracellular α-synuclein exists as high molecular weight species.ConclusionsThe present study uncovers a novel regulatory pathway associated with α-synuclein release, whose dysregulation might affect various pathological actions of extracellular α-synuclein including its trans-synaptic propagation.
Highlights
The pathological aggregation of α-synuclein characterizes Parkinson’s disease, dementia with Lewy bodies and multiple system atrophy collectively referred to as α-synucleinopathies [1, 2]
Consistent with the hypothesis, we found that tetrodotoxin (TTX), a sodium channel blocker that inhibits the generation of action potential, significantly decreased α-synuclein levels released in media (Fig. 1a)
This demonstrates that neuronal activity influenced extracellular α-synuclein levels by modulating the release, not by augmenting excitotoxicity or altering its expression level
Summary
The pathological aggregation of α-synuclein characterizes Parkinson’s disease, dementia with Lewy bodies and multiple system atrophy collectively referred to as α-synucleinopathies [1, 2]. Α-Synuclein is present in media of various cells overexpressing α-synuclein and peripheral neurons [6, 11, 14, 15], brain interstitial fluid (ISF) [16] and in cerebrospinal fluid [17, 18], suggesting that its release occurs independently of cell death. The phenomenon of αsynculein release has been well documented, whereas the underlying mechanism that regulates α-synuclein release has remained poorly investigated. To better understand the physiological release of α-synuclein, we have examined the relationship between neuronal activity and α-synuclein release both in cultured neurons and living mice
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