Objective: To investigate the significance of Lewy body pathology (LBP) in relation to midbrain molecular and cellular changes associated with Parkinson’s disease (PD).
Background: The molecular and cellular mechanisms underlying the early stages of PD, particularly before the appearance of Lewy bodies (LBs), are not well understood. Incidental Lewy body disease (iLBD), which is characterized by brainstem-dominant LBP in the absence of clinical PD, is considered a potential pathological precursor to PD. As such, iLBD provides a unique opportunity to examine transcriptomic and proteomic changes that precede the onset of symptomatic PD.
Method: We performed a multi-omic analysis of post-mortem midbrain tissue from age- and sex-matched unaffected individuals, iLBD cases, PD cases, and ApoE-matched Alzheimer’s disease (AD) cases, both with and without LBP (AD and AD+LBP). We utilized spatial transcriptomics, proteomics, and αSyn seed amplification assays (SAA) to map molecular alterations along the trajectory of LBP progression.
Results: Gene and protein expression changes correlated with Braak LB stage and SAA metrics in both iLBD and PD cases. Multiple molecular and cellular changes were detected in the substantia nigra pars compacta (SNpc) of iLBD cases, despite the absence of apparent LBP. In contrast, no significant changes were observed in AD cases, with or without LBP, suggesting that misfolded αSyn alone is insufficient to drive pathology in the SNpc. A notable finding was the upregulation of C1QC, a key microglial synaptic pruning signal, in iLBD cases. This signal preferentially localized to inhibitory GABAergic synapses rather than dopaminergic (DA) synapses, indicating early synaptic dysfunction before neuronal loss and αSyn aggregation in PD.
Conclusion: Our findings suggest that microglia-mediated synaptic remodeling occurs early in the pathogenesis of PD and may represent a potential therapeutic target for early intervention.
Figure 1
References: Koeglsperger, T. et al. Neuropathology of incidental Lewy body & prodromal Parkinson’s disease. Mol Neurodegener 18, 32 (2023).
To cite this abstract in AMA style:
S. Rumpf, F. Strübing, K. Nalbach, S. Lichtenthaler, C. Vargiu, P. Parchi, G. Höglinger, J. Herms, T. Koeglsperger. Spatial Multi-Omics Identifies Early Synaptic Pruning and Context-Specific Dopaminergic Vulnerability in Synucleinopathies [abstract]. Mov Disord. 2025; 40 (suppl 1). https://www.mdsabstracts.org/abstract/spatial-multi-omics-identifies-early-synaptic-pruning-and-context-specific-dopaminergic-vulnerability-in-synucleinopathies/. Accessed October 5, 2025.« Back to 2025 International Congress
MDS Abstracts - https://www.mdsabstracts.org/abstract/spatial-multi-omics-identifies-early-synaptic-pruning-and-context-specific-dopaminergic-vulnerability-in-synucleinopathies/