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

Area of Science:

• Neuroscience
• Molecular Biology
• Pathology

Background:

• Parkinson's disease (PD) involves dopaminergic neuron loss in the substantia nigra, but early molecular triggers are unknown.
• Alpha-synuclein (αSyn) aggregation is a hallmark, but its precise role in initiating neurodegeneration is debated.
• Understanding early events is crucial for developing preventative Parkinson's disease therapies.

Purpose of the Study:

• To investigate the molecular and pathological events preceding neurodegeneration in Parkinson's disease spectrum disorders.
• To differentiate the role of αSyn pathology in PD versus Alzheimer's disease with Lewy body pathology (AD+LBP).
• To identify early biomarkers and pathogenic mechanisms in incidental Lewy body disease (iLBD).

Main Methods:

• Combined spatial transcriptomics, spatial proteomics, and α-synuclein (αSyn) seed amplification assays.
• Profiled post-mortem midbrain tissues from control, iLBD, PD, AD, and AD+LBP groups.
• Correlated αSyn seeding activity with dopaminergic neuron loss and synaptic marker expression.

Main Results:

• αSyn seeding activity correlated with dopaminergic neuron loss in PD-spectrum cases, but not in AD+LBP.
• In iLBD, increased C1QC expression and loss of inhibitory synaptic markers were observed before overt αSyn pathology.
• These early changes suggest a role for complement activation and synaptic remodeling in PD pathogenesis.

Conclusions:

• The relationship between αSyn pathology and neurodegeneration is disease-context dependent.
• Early complement-associated remodeling of inhibitory synapses may precede αSyn aggregation and neuronal loss in Parkinson's disease.
• These findings offer potential early diagnostic markers and therapeutic targets for Parkinson's disease.