The making of a Lewy body: the role of alpha-synuclein post-fibrillization modifications in regulating the formation and the maturation of pathological inclusions.
Anne‐Laure Mahul‐MellieriD, Melek Firat AltayiD, Johannes BurtscheriD, Niran MaharjaniD, Nadine Ait‐BouziadiD, Anass ChikiiD, Siv VingilliD, Richard Wade‐MartinsiD, Janice L. HoltoniD, Catherine Strand, Caroline HaikaliD, Jiayi LiiD, Romain HameliniD, Marie Croisier, Graham William KnottiD, Georges Mairet‐Coello, Laura Weerens, Anne MicheliD, Patrick Mark Downey, Martin CitroniD, Hilal Ahmed LashueliD
Abstract
Although converging evidence point to alpha-synuclein (a-syn) aggregation and Lewy body (LB) formation as central events in Parkinson's disease (PD), the molecular mechanisms that regulate these processes and their role in disease pathogenesis remain poorly understood. Herein, we applied an integrative biochemical, structural and imaging approach to elucidate the sequence, molecular and cellular mechanisms that regulate LB formation in primary neurons. Our results establish that post-fibrillization C-terminal truncation mediated by calpains 1 and 2 and potentially other enzymes, plays critical roles in regulating a-syn seeding, fibrillization and orchestrates many of the events associated with LB formation and maturation. These findings combined with the abundance of a-syn truncated species in LBs and pathological a-syn aggregates have significant implications for ongoing efforts to develop therapeutic strategies based on targeting the C-terminus of a-syn or proteolytic processing of this region.
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Abstract summary
Claude Opus 5.5 · xhigh effort · 18 Oct 2026 · from the abstract
Calpain-1/2 cleavage of the alpha-synuclein C-terminus after fibril formation is reported to drive seeding, aggregation and the maturation of Lewy-body-like inclusions in primary neurons.
Lewy bodies are a defining feature of Parkinson's disease, yet how alpha-synuclein aggregates are converted into them is still poorly understood. Putting proteolytic removal of the C-terminus after fibril formation at the centre of that conversion bears directly on therapies aimed at the alpha-synuclein C-terminus or at the enzymes that cut it.
Key results
ClaimedC-terminal truncation that happens after alpha-synuclein has already fibrillized, mediated by calpains 1 and 2 and possibly other enzymes, is placed upstream of seeding and further fibrillization in primary neurons.
Presented as the conclusion of a combined biochemical, structural and imaging study in primary neurons; the abstract reports no measurements, effect sizes or comparisons. · Abstract
ClaimedThe same post-fibrillization cleavage step is said to coordinate many of the events by which aggregates form and mature into Lewy-body-like inclusions.
Stated as an outcome of tracking the sequence of molecular and cellular events in the primary-neuron model; no quantification of inclusion formation or maturation appears in the abstract. · Abstract
ClaimedThe authors tie the mechanism to the reported abundance of truncated alpha-synuclein in Lewy bodies and pathological aggregates, and argue it matters for drug programmes targeting the C-terminus or its processing.
An interpretive statement in the abstract; neither the abundance measurement nor any therapeutic test is described there. · Abstract
Methods, data and reproducibility
Combined biochemical, structural and imaging analyses in primary neurons, used to order the molecular and cellular events that follow alpha-synuclein fibril formation and lead to Lewy-body-like inclusions, with attention to proteolytic processing of the fibrillar protein.
- primary neurons in which alpha-synuclein aggregation and inclusion formation were followed
Limitations (2)
- Abstract only: no quantitative data, controls or effect sizes are given for any of the mechanistic conclusions, so the contribution of calpain-mediated truncation cannot be weighed from the text available. · noted in this summary
- The mechanism is characterised in cultured primary neurons; the abstract does not establish that the same post-fibrillization processing governs inclusion maturation in human brain. · noted in this summary
Who should read:Read this if you work on alpha-synuclein aggregation, Lewy body biology or protease-directed therapeutics and want the case that C-terminal cleavage after fibril formation drives inclusion maturation.
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