Objective: To identify early molecular and cellular changes associated with dopaminergic neuron vulnerability and synuclein pathology across different disease contexts.

Background: Parkinson’s disease (PD) is characterized by degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc), yet the molecular events preceding neuronal loss remain poorly understood. Lewy body pathology (LBP) is considered a central driver of PD, but LBP can occur without accompanying neurodegeneration, suggesting that additional context-dependent mechanisms contribute to disease progression.

Method: We combined spatial transcriptomics, spatial proteomics, and α-synuclein (αSyn) seed amplification assays to profile post-mortem midbrain tissue from neurologically normal individuals, incidental Lewy body disease (iLBD), PD, Alzheimer’s disease (AD), and AD with LBP.

Results: Across disease contexts, αSyn seeding activity correlated strongly with dopaminergic neuron loss in PD-spectrum cases but not in AD-associated LBP, indicating that the relationship between αSyn pathology and neurodegeneration is disease-context dependent. Notably, in prodromal iLBD—before overt SNpc Lewy pathology or detectable αSyn seeding—we observed a marked increase in the complement component C1QC. Spatial analyses associated C1QC enrichment with microglial and inhibitory neuronal signatures. Immunohistochemical analyses further revealed a reduction of GABAergic terminals in both iLBD and PD, suggesting early complement-mediated remodeling of inhibitory synapses in the SNpc.

Conclusion: These findings support a model in which microglia-associated complement signaling drives early synaptic remodeling of inhibitory inputs onto dopaminergic neurons prior to overt αSyn aggregation and neuronal degeneration. Complement-mediated synaptic remodeling may therefore represent an early pathogenic mechanism and a potential therapeutic target in PD.

References: 1. Rumpf, S.-L. et al. Spatial Multi-Omics Identifies Early Synaptic Pruning and Context-Specific Dopaminergic Vulnerability in Synucleinopathies. (2025) doi:10.21203/rs.3.rs-7852229/v1., Nature Communications, under revision.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/early-complement-activation-prunes-inhibitory-synapses-in-prodromal-synucleinopathy-independent-from-lewy-pathology/