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Peer-reviewedCC BYNature Communications

Ultrastructural diversity and subcellular organization of nigral Lewy pathology in Parkinson’s disease

  • Amanda J. Lewis1,2
  • Lukas van den Heuvel3,4
  • Marta Di Fabrizio3,4
  • Kaliya Bandelier4
  • Daria Proniakova4
  • Domenic Burger3,5,4
  • Notash Shafiei3,4
  • Kazadi Ekundayo3,4
  • Selene Offringa4
  • Evelien Huisman6
  • John G. J. M. Bol6
  • Wilma D. J. van de Berg7,6
1 more authors
  • Henning Stahlberg3,4
7 affiliations
  1. 1Department of Fundamental Microbiology, University of Lausanne, Lausanne, Switzerland. [email protected]
  2. 2Laboratory of Biological Electron Microscopy, School of Basic Sciences, Federal Institute of Technology Lausanne (EPFL), Lausanne, Switzerland. [email protected]
  3. 3Department of Fundamental Microbiology, University of Lausanne, Lausanne, Switzerland
  4. 4Laboratory of Biological Electron Microscopy, School of Basic Sciences, Federal Institute of Technology Lausanne (EPFL), Lausanne, Switzerland
  5. 5F. Hoffmann-La Roche Ltd, Pharma Research and Early Development, Grenzacherstrasse 124, Basel, Switzerland
  6. 6Department of Anatomy and Neurosciences, section Clinical Neuroanatomy and Biobanking, Amsterdam Neuroscience, Amsterdam University Medical Centre, Vrije University Amsterdam, Amsterdam, The Netherlands
  7. 7Amsterdam Neuroscience program Neurodegeneration, Amsterdam University Medical Centre, Vrije University Amsterdam, Amsterdam, The Netherlands
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Abstract

Lewy bodies, the defining pathological feature of Parkinson’s disease, are intraneuronal inclusions enriched in aggregated alpha-synuclein (αSyn). We used correlative light and electron microscopy to selectively investigate phosphorylated αSyn (αSyn pS129 )-positive inclusions in the substantia nigra of end-stage postmortem Parkinson’s disease brain. Here we show that somatic αSyn pS129 inclusions in nigral dopaminergic neurons are consistently fibrillar, whereas the membranous-type inclusions are restricted to neuritic processes. These neuritic inclusions displayed marked ultrastructural heterogeneity, ranging from predominantly membranous to mixed membranous-fibrillar forms. The selective targeting of defined inclusions enabled detailed structural characterization of Lewy pathology, rather than quantitative or disease-stage comparisons. Our findings highlight clear ultrastructural differences between somatic and neuritic αSyn pS129 pathology and demonstrate the structural complexity and heterogeneity of Lewy pathology in human Parkinson’s disease brain.

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Cite

BibTeXRIS
BibTeX
@article{lewis2026ultrastructural,
  title = {{Ultrastructural diversity and subcellular organization of nigral Lewy pathology in Parkinson’s disease}},
  author = {Amanda J. Lewis and Lukas van den Heuvel and Marta Di Fabrizio and Kaliya Bandelier and Daria Proniakova and Domenic Burger and Notash Shafiei and Kazadi Ekundayo and Selene Offringa and Evelien Huisman and John G. J. M. Bol and Wilma D. J. van de Berg and Henning Stahlberg},
  journal = {Nature Communications},
  year = {2026},
  month = jun,
  doi = {10.1038/s41467-026-74083-z},
  url = {https://doi.org/10.1038/s41467-026-74083-z},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Ultrastructural diversity and subcellular organization of nigral Lewy pathology in Parkinson’s disease
AU  - Amanda J. Lewis
AU  - Lukas van den Heuvel
AU  - Marta Di Fabrizio
AU  - Kaliya Bandelier
AU  - Daria Proniakova
AU  - Domenic Burger
AU  - Notash Shafiei
AU  - Kazadi Ekundayo
AU  - Selene Offringa
AU  - Evelien Huisman
AU  - John G. J. M. Bol
AU  - Wilma D. J. van de Berg
AU  - Henning Stahlberg
PY  - 2026
DA  - 2026/06/08
JO  - Nature Communications
DO  - 10.1038/s41467-026-74083-z
UR  - https://doi.org/10.1038/s41467-026-74083-z
AB  - Lewy bodies, the defining pathological feature of Parkinson’s disease, are intraneuronal inclusions enriched in aggregated alpha-synuclein (αSyn). We used correlative light and electron microscopy to selectively investigate phosphorylated αSyn (αSyn pS129 )-positive inclusions in the substantia nigra of end-stage postmortem Parkinson’s disease brain. Here we show that somatic αSyn pS129 inclusions in nigral dopaminergic neurons are consistently fibrillar, whereas the membranous-type inclusions are restricted to neuritic processes. These neuritic inclusions displayed marked ultrastructural heterogeneity, ranging from predominantly membranous to mixed membranous-fibrillar forms. The selective targeting of defined inclusions enabled detailed structural characterization of Lewy pathology, rather than quantitative or disease-stage comparisons. Our findings highlight clear ultrastructural differences between somatic and neuritic αSyn pS129 pathology and demonstrate the structural complexity and heterogeneity of Lewy pathology in human Parkinson’s disease brain.
SN  - 2041-1723
ER  -