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, but the link between synucleinopathy and neurodegeneration is unclear.
• Complement cascade activation is observed in PD, but its role as a cause or consequence of neurodegeneration is debated.

Purpose of the Study:

• To investigate if pathological α-syn directly activates the complement cascade prior to neurodegeneration in Parkinson's disease.
• To elucidate the temporal relationship between α-syn aggregation, complement activation, and neuronal damage.

Main Methods:

• Utilized a rat α-syn preformed fibril (PFF) model exhibiting temporal separation between aggregation and degeneration.
• Performed in vitro complement assays and analyzed postmortem human PD brain tissue.
• Quantified complement components, receptors, regulators, and α-syn burden during early synucleinopathy.

Main Results:

• Synucleinopathy induced complement activation, including classical and alternative pathway components, and complement receptors, preceding nigrostriatal degeneration.
• Microglial C3 upregulation correlated with α-syn burden, while complement regulators (Cd55, Cd59, Nptx1) were downregulated in affected brain regions.
• Aggregated α-syn directly bound C1q, initiating complement cascade activation in a C1q-dependent manner, findings supported by human PD tissue analysis.

Conclusions:

• Pathological α-syn directly triggers complement cascade activation and dysregulation early in the disease process, before overt neurodegeneration.
• This study provides the first in vivo evidence linking α-syn aggregation to complement activation as a potential driver of Parkinson's disease pathogenesis.