Objective: To investigate the specific effects of the core complement component C4 on α-synuclein aggregation and neuroinflammation during the pathogenesis of PD.

Background: Synucleinopathies are characterized by the accumulation of α-synuclein (α-syn), primarily in the form of Lewy bodies (LBs) within dopaminergic neurons. The accumulation of α-Syn leads to the gradual loss of neurons in the basal ganglia of patients, and the presence of reactive microglia in the areas of neuronal loss indicates that neuroinflammation is a core feature¹. α-syn can activate the classical complement pathway, and the complement system is involved in α-syn-dependent cytotoxicity², however, the mechanisms by which the complement system participates in α-syn-induced neurodegeneration remain unclear.

Method: This study used mice with stereotaxic injection of α-syn PFF or mixture of C4 and α-syn PFF into the striatum as animal models. Levels of pro-inflammatory cytokines IL-1β, IL-6, and TNF-α of midbrain were assessed using qPCR and Western blot. Mouse motor function was evaluated through Rotarod test, and Pole test. The levels of TH and phosphorylated α-syn in the substantia nigra and striatum of mice were detected using immunofluorescence and immunohistochemical staining.

Results: Behavioral tests showed significant motor deficits in mice injected with α-syn PFF + C4 compared to α-syn PFF or PBS groups. Immunohistochemistry revealed greater dopaminergic neuronal loss in the SN and striatum of α-syn PFF + C4 mice. qPCR and Western blot analysis indicated elevated pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) and reduced TH protein levels, suggesting severe neuroinflammation and dopaminergic damage (Figures 1). Immunofluorescence and immunohistochemical staining further demonstrated increased α-syn aggregation and dopaminergic neuron loss in α-syn PFF + C4 mice compared to PBS or α-syn PFF alone (Figures 2).

Conclusion: Complement C4 exacerbated motor dysfunction, neuroinflammation, dopaminergic neuronal loss, and α-syn pathology in α-syn PFF-injected mice. These findings reveal that complement C4 significantly contributes to the neuroinflammatory environment and α-syn pathology in PD, highlighting its potential as a therapeutic target for mitigating neurodegeneration in this disorder.

C4 exacerbates inflammation and neurotoxicity

C4 promotes the aggregation and spread of α-syn

References: 1. Tansey MG, Wallings RL, Houser MC, Herrick MK, Keating CE, Joers V. Inflammation and immune dysfunction in Parkinson disease. Nat Rev Immunol. Nov 2022;22(11):657-673. doi:10.1038/s41577-022-00684-6
2. Gregersen E, Betzer C, Kim WS, et al. Alpha-synuclein activates the classical complement pathway and mediates complement-dependent cell toxicity. J Neuroinflammation. Aug 16 2021;18(1):177. doi:10.1186/s12974-021-02225-9

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MDS Abstracts - https://www.mdsabstracts.org/abstract/complement-c4-exacerbates-inflammation-and-neuronal-damage-in-vivo/