Lewy bodies are full of lipids and organelles

The research record

This is the project's file for this landmark, as written and checked. Sources are listed at the end; anything not yet confirmed is marked "Not yet verified".

Who

Sarah Shahmoradian, Amanda Lewis and 31 co-authors from Basel, Amsterdam and other centres, including Wilma van de Berg (Amsterdam UMC), Henning Stahlberg (Basel) and Matthias Lauer (last author). Funding was not confirmed beyond a US NIH grant (R01 GM081653) listed in Europe PMC.

What happened

Lewy bodies (the round inclusions inside neurons that define Parkinson's; see landmark 21) were assumed to be dense bundles of alpha-synuclein fibrils (landmark 5). The team tagged alpha-synuclein-positive inclusions in postmortem brain, then imaged the same spots with electron microscopy and tomography (3D electron imaging). They saw a "crowded" mix of membrane fragments, vesicles, lysosome-like structures and misshapen mitochondria. Filaments appeared in many but not all inclusions. Alzforum reported five donors, 17 Lewy bodies and three Lewy neurites, with only 3 of the 17 Lewy bodies filled with filaments (the preprint counted 16 inclusions). Super-resolution (STED) microscopy, infrared imaging and lipid analysis (lipidomics) indicated high lipid content. Nature Neuroscience 22(7):1099–1109, 2019.

Why it moved us toward a cure

It asks a different question: what is alpha-synuclein doing to membranes and organelles, rather than only how it forms fibrils. If damage to membrane trafficking and mitochondria is central, drugs aimed only at fibrils might miss part of the target. It fits the lipid and lysosome genes found elsewhere (landmark 35, landmark 19).

Outcome

Open. Reaction at a 2019 Lisbon conference, reported by Alzforum, was mixed. Some attendees suspected the lipid signal came from tissue processing; the authors said their controls excluded this. A commenter noted that phospholipids in Lewy inclusions had been reported in 1969. A separate STED study from the same Amsterdam group (Moors et al., Acta Neuropathol 2021;142:423–448, DOI 10.1007/s00401-021-02329-9) found layered Lewy bodies with a phosphorylated-synuclein framework (landmark 94). A cryo-electron-tomography study of seeded mouse neurons (Trinkaus et al., Nat Commun 2021;12:2110, DOI 10.1038/s41467-021-22108-0) found fibrils crossing organelles without binding their membranes; it used recombinant or MSA-patient seeds, not Parkinson's tissue. Whether the paper's small sample (a handful of donors) holds in larger cohorts is unresolved. I found no retraction or correction; the paper drew three commentaries (Nat Rev Neurosci, Brain editorial and others).

Sources

• Shahmoradian et al., Nat Neurosci 2019;22:1099–1109, DOI 10.1038/s41593-019-0423-2 (Basel repository) · Amsterdam UMC record
• bioRxiv preprint (donor and inclusion counts)
• Basel press release, 27 Jun 2019
• Alzforum, "Forget Fibrils: Lewy Pathology Is More Lipid Than Protein", 10 May 2019
• Moors et al., Acta Neuropathol 2021, DOI 10.1007/s00401-021-02329-9
• Trinkaus et al., Nat Commun 2021, ASAP summary
• Not yet verified: exact donor and inclusion counts in the published version (preprint says 16 inclusions, Alzforum 17 plus 3 neurites); independent replication in human Parkinson's tissue; the Trinkaus journal details beyond the ASAP summary.