Complement Dysregulation During the Early Phases of Synucleinopathy

Area of Science:

• Neuroscience
• Immunology
• Pathology

Background:

• Parkinson's disease (PD) involves alpha-synuclein (α-syn) aggregation and neuroinflammation.
• The role of complement activation in PD pathogenesis, particularly its timing relative to neurodegeneration, is unclear.

Purpose of the Study:

• To investigate whether pathological α-syn directly activates the complement cascade prior to neurodegeneration in PD.
• To elucidate the immune mechanisms linking synucleinopathy to neurodegeneration.

Main Methods:

• Utilized a rat α-syn preformed fibril (PFF) model with temporal separation of aggregation and degeneration.
• Performed in vitro complement assays and analyzed human postmortem PD brain tissue.
• Quantified complement expression, activation, and regulatory protein levels during early synucleinopathy.

Main Results:

• Synucleinopathy induced complement activation (classical and alternative pathways) before nigrostriatal degeneration.
• Microglial C3 upregulation correlated with synucleinopathy burden.
• Complement regulatory proteins (CD55, CD59, Nptx1) were downregulated in affected brain regions.
• Aggregated α-syn directly binds C1q and initiates complement activation.

Conclusions:

• Synucleinopathy triggers complement activation and dysregulation preceding neurodegeneration in PD.
• Findings in the rat model were supported by observations in human PD brain tissue.
• Direct activation of complement by aggregated α-syn provides a mechanistic link between pathology and immune response in PD.