Objective:

To investigate complement activation during the early stages of synucleinopathy and determine if pathological α-synuclein directly activates complement prior to overt neurodegeneration.

Approach:

• Study Model: Utilized the rat α-syn preformed fibril (PFF) model to quantify complement expression and activation during the aggregation phase.
• Complement Activation Assessment: Measured upregulation of genes in the classical and alternative complement pathways, activation of C3, and downregulation of complement regulators.
• Human Tissue Validation: Validated findings in human postmortem PD substantia nigra tissue.

Key Findings:

• Robust complement activation occurs prior to overt neurodegeneration in the rat model.
• Significant upregulation of complement genes and activation of C3 correlates with synucleinopathy burden.
• Specific complement regulators, such as CD55 and NPTX1, are downregulated in the substantia nigra of PD patients.
• Aggregated α-synuclein directly binds C1q and activates the classical complement system.

Interpretation:

Pathological α-synuclein can directly activate the complement system during the early stages of synucleinopathy.

Limitations:

• The study primarily utilizes a rat model, which may not fully replicate human disease.
• The investigation focuses on early stages and does not address later stages of neurodegeneration.

Conclusion:

Evidence of early complement system dysregulation in response to pathological α-synuclein is provided.