Extracellular α-synuclein levels are regulated by neuronal activity

Area of Science:

• Neuroscience
• Cell Biology
• Biochemistry

Background:

• Alpha-synuclein (α-synuclein) is a presynaptic neuronal protein found in both intracellular and extracellular spaces.
• Extracellular α-synuclein contributes to cellular toxicity, synaptic dysfunction, and pathology propagation.
• The regulation of extracellular α-synuclein levels remains largely unknown.

Purpose of the Study:

• To investigate the role of neuronal and synaptic activity in regulating the release of endogenous α-synuclein.
• To identify the primary mechanisms governing extracellular α-synuclein levels.

Main Methods:

• Utilized primary neuronal cultures and in vivo microdialysis in mice.
• Modulated neuronal and synaptic activities using mechanistically distinct approaches.
• Examined the impact of glutamatergic neurotransmission modulation on α-synuclein release.

Main Results:

• Physiological α-synuclein release is highly dependent on neuronal activity; increased activity enhances release, while decreased activity reduces it.
• Approximately 70% of extracellular α-synuclein originates from a neuronal activity-dependent pathway.
• Modulating glutamatergic neurotransmission affects extracellular α-synuclein levels, and synaptic vesicle exocytosis can trigger α-synuclein release.
• Extracellular α-synuclein was observed to exist as high molecular weight species.

Conclusions:

• Identified a novel regulatory pathway for α-synuclein release linked to neuronal activity.
• Dysregulation of this pathway may influence extracellular α-synuclein's pathological roles, including trans-synaptic propagation.