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<p>Parkinson’s disease (PD) is characterized by degeneration of dopaminergic neurons in the substantia nigra pars compacta, but the molecular events preceding neuronal loss remain unclear. Here, we combine spatial transcriptomics, spatial proteomics, and α-synuclein (αSyn) seed amplification assays to profile post-mortem midbrain tissue from controls, incidental Lewy body disease (iLBD), PD, Alzheimer’s disease (AD), and AD with Lewy body pathology (AD + LBP). We find that αSyn seeding activity correlates with dopaminergic neuron loss in PD-spectrum cases but not in AD-associated LBP, indicating disease-context dependent relationships between αSyn pathology and neurodegeneration. In iLBD, before overt substantia nigra Lewy pathology or detectable αSyn aggregation, we detect increased expression of the complement component C1QC together with loss of inhibitory synaptic markers. These findings support early complement-associated remodeling of inhibitory synapses as a potential pathogenic event preceding overt αSyn aggregation and neuronal degeneration in PD.</p>

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Spatial multi-omics identifies early synaptic pruning and context-specific dopaminergic vulnerability in synucleinopathies

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月21日

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  • Svenja-Lotta Rumpf,
  • Felix L. Strübing,
  • Karsten Nalbach,
  • Claudia Marina Vargiu,
  • Giacomo Berg,
  • Stefan F. Lichtenthaler,
  • Piero Parchi,
  • Pan Gao,
  • Weilin Chen,
  • Matthias Brendel,
  • Johannes S. Gnörich,
  • Alexander Bernhardt,
  • Léa Dias Rodrigues,
  • Günter U. Höglinger,
  • Jochen Herms,
  • Thomas Koeglsperger

摘要

Parkinson’s disease (PD) is characterized by degeneration of dopaminergic neurons in the substantia nigra pars compacta, but the molecular events preceding neuronal loss remain unclear. Here, we combine spatial transcriptomics, spatial proteomics, and α-synuclein (αSyn) seed amplification assays to profile post-mortem midbrain tissue from controls, incidental Lewy body disease (iLBD), PD, Alzheimer’s disease (AD), and AD with Lewy body pathology (AD + LBP). We find that αSyn seeding activity correlates with dopaminergic neuron loss in PD-spectrum cases but not in AD-associated LBP, indicating disease-context dependent relationships between αSyn pathology and neurodegeneration. In iLBD, before overt substantia nigra Lewy pathology or detectable αSyn aggregation, we detect increased expression of the complement component C1QC together with loss of inhibitory synaptic markers. These findings support early complement-associated remodeling of inhibitory synapses as a potential pathogenic event preceding overt αSyn aggregation and neuronal degeneration in PD.