Journal Article

DZNE-2026-00798

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Spatial multi-omics identifies early synaptic pruning and context-specific dopaminergic vulnerability in synucleinopathies.

Rumpf, S.-L. (First author)DZNE* ; Strübing, F. L. (First author)DZNE* ; Nalbach, K.DZNE* ; Vargiu, C. M. ; Berg, G.DZNE* ; Lichtenthaler, S. F.DZNE* ; Parchi, P. ; Gao, P.DZNE* ; Chen, W.DZNE* ; Brendel, M.Extern* ; Gnörich, J. S.DZNE* ; Bernhardt, A. M.Extern* ; Dias Rodrigues, L.DZNE* ; Höglinger, G. U.DZNE* ; Herms, J.DZNE* ; Köglsperger, T. (Last author)DZNE*

2026
Springer Nature [London]

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Please use a persistent id in citations: doi:10.1038/s41467-026-74961-6

Abstract: 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.

Keyword(s): Humans (MeSH) ; alpha-Synuclein: metabolism (MeSH) ; alpha-Synuclein: genetics (MeSH) ; Dopaminergic Neurons: metabolism (MeSH) ; Dopaminergic Neurons: pathology (MeSH) ; Parkinson Disease: pathology (MeSH) ; Parkinson Disease: metabolism (MeSH) ; Parkinson Disease: genetics (MeSH) ; Proteomics: methods (MeSH) ; Synapses: metabolism (MeSH) ; Synapses: pathology (MeSH) ; Alzheimer Disease: pathology (MeSH) ; Alzheimer Disease: metabolism (MeSH) ; Alzheimer Disease: genetics (MeSH) ; Synucleinopathies: metabolism (MeSH) ; Synucleinopathies: pathology (MeSH) ; Synucleinopathies: genetics (MeSH) ; Male (MeSH) ; Spatial Transcriptomics (MeSH) ; Lewy Body Disease: pathology (MeSH) ; Lewy Body Disease: metabolism (MeSH) ; Lewy Body Disease: genetics (MeSH) ; Female (MeSH) ; Aged (MeSH) ; Multiomics (MeSH) ; Neuronal Plasticity (MeSH) ; Complement C1q: metabolism (MeSH) ; Substantia Nigra: pathology (MeSH) ; Substantia Nigra: metabolism (MeSH) ; Aged, 80 and over (MeSH) ; Mesencephalon: metabolism (MeSH) ; Mesencephalon: pathology (MeSH) ; alpha-Synuclein ; Complement C1q

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Contributing Institute(s):

1. Clinical Research (Munich) (Clinical Research (Munich))
2. Translational Brain Research (AG Herms)
3. Neuroproteomics (AG Lichtenthaler)
4. Molecular Neurodegeneration (AG Haass)

Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)
2. 352 - Disease Mechanisms (POF4-352) (POF4-352)

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