Extracellular Alpha-Synuclein Promotes a Neuroinhibitory Secretory Phenotype in Astrocytes

Area of Science:

• Neuroscience
• Cell Biology
• Pathology

Background:

• Multiple system atrophy (MSA) and dementia with Lewy bodies (DLB) are α-synucleinopathies characterized by neuroinflammation and astrogliosis.
• Activated astrocytes display increased Munc18, a protein vital for vesicle exocytosis.

Purpose of the Study:

• To investigate the link between extracellular α-synuclein and the development of a secretory astrocyte phenotype.
• To understand the role of astrocytes in the neuroinflammatory response in α-synucleinopathies.

Main Methods:

• Immunofluorescence on human brain tissue from MSA, DLB, and control subjects.
• In vitro studies using the 1321N1 astrocytoma cell line treated with α-synuclein.
• Co-culture experiments with primary rat astrocytes and neurons.

Main Results:

• Activated astrocytes in MSA and DLB tissues showed increased Munc18-positive vesicles compared to controls.
• α-synuclein treatment upregulated Munc18 vesicles, GFAP expression, and IL-6 secretion in astrocytoma cells.
• Astrocytes pretreated with α-synuclein inhibited neurite growth and upregulated chondroitin sulphate proteoglycan in co-cultured neurons.

Conclusions:

• Extracellular α-synuclein significantly upregulates the secretory machinery in astrocytes.
• This astrocyte response may contribute to the release of neuroinhibitory and proinflammatory factors in α-synucleinopathies.