Dissecting the differential role of C-terminal truncations in the regulation of aSyn pathology formation and the biogenesis of Lewy bodies Article Swipe
Anne-Laure Mahul-Mellier
,
Melek Firat Altay
,
Niran Maharjan
,
Nadine Ait‐Bouziad
,
Anass Chiki
,
Somanath Jagannath
,
Galina Limorenko
,
Salvatore Novello
,
Jonathan Ricci
,
Siv Vingill
,
Richard Wade‐Martins
,
Janice L. Holton
,
Catherine Strand
,
Caroline Haikal
,
Jiayi Li
,
Romain Hamelin
,
Mary-Claude Croisier
,
Graham Knott
,
Georges Mairet‐Coello
,
Anne Michel
,
Patrick Downey
,
Martin Citron
,
Hilal A. Lashuel
·
YOU?
·
· 2024
· Open Access
·
· DOI: https://doi.org/10.1101/2024.11.29.625993
YOU?
·
· 2024
· Open Access
·
· DOI: https://doi.org/10.1101/2024.11.29.625993
Alpha-synuclein (aSyn) post-translational modifications (PTMs), particularly phosphorylation at serine 129 and C-terminal truncations, are highly enriched in Lewy bodies (LBs), Lewy neurites, and other types of aSyn pathological aggregates in the brain of patients with Parkinson’s disease (PD) and other synucleinopathies. However, our knowledge about the precise role of PTMs in regulating the different stages of pathology formation, neurodegeneration, and aSyn pathology spreading remains incomplete. In this work, we applied a systematic approach to address this knowledge gap with an emphasis on mapping and elucidating the role of post-fibrillization C-terminal aSyn truncations in regulating the uptake, processing, seeding activity, and formation of LB-like inclusions and maturations in a well-established neuronal seeding model that recapitulates all the stages leading to LB formation and neurodegeneration. Our work shows that C-terminal cleavage of aSyn fibrils at multiple sites is a conserved process that occurs rapidly after and during the formation of intracellular LB-like aSyn inclusions in all neuronal seeding models. Interestingly, blocking the cleavage of internalized fibrils does not influence their seeding activity, whereas inhibiting the enzymes that regulate the cleavage of newly formed fibrils (e.g., calpains 1 and 2) significantly alters the formation of LB-like inclusions. We also show that C-terminal truncations, in combination with other PTMs, play a crucial role in regulating the interactome and remodeling of newly formed aSyn fibrils, including their shortening, lateral association, and packing during LB formation and maturation. Altogether, our results demonstrate that post-fibrillization C-terminal truncations have a differential role at different stages of aSyn aggregation and pathology formation. These insights, combined with the abundance of truncated aSyn species in LBs, have significant implications in understanding aSyn pathological diversity and developing therapeutic strategies targeting the C-terminus of aSyn or its proteolytic processing.
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- Type
- preprint
- Language
- en
- Landing Page
- https://doi.org/10.1101/2024.11.29.625993
- https://www.biorxiv.org/content/biorxiv/early/2024/11/30/2024.11.29.625993.full.pdf
- OA Status
- green
- Cited By
- 4
- References
- 133
- Related Works
- 10
- OpenAlex ID
- https://openalex.org/W4404882037
All OpenAlex metadata
Raw OpenAlex JSON
- OpenAlex ID
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https://openalex.org/W4404882037Canonical identifier for this work in OpenAlex
- DOI
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https://doi.org/10.1101/2024.11.29.625993Digital Object Identifier
- Title
-
Dissecting the differential role of C-terminal truncations in the regulation of aSyn pathology formation and the biogenesis of Lewy bodiesWork title
- Type
-
preprintOpenAlex work type
- Language
-
enPrimary language
- Publication year
-
2024Year of publication
- Publication date
-
2024-11-30Full publication date if available
- Authors
-
Anne-Laure Mahul-Mellier, Melek Firat Altay, Niran Maharjan, Nadine Ait‐Bouziad, Anass Chiki, Somanath Jagannath, Galina Limorenko, Salvatore Novello, Jonathan Ricci, Siv Vingill, Richard Wade‐Martins, Janice L. Holton, Catherine Strand, Caroline Haikal, Jiayi Li, Romain Hamelin, Mary-Claude Croisier, Graham Knott, Georges Mairet‐Coello, Anne Michel, Patrick Downey, Martin Citron, Hilal A. LashuelList of authors in order
- Landing page
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https://doi.org/10.1101/2024.11.29.625993Publisher landing page
- PDF URL
-
https://www.biorxiv.org/content/biorxiv/early/2024/11/30/2024.11.29.625993.full.pdfDirect link to full text PDF
- Open access
-
YesWhether a free full text is available
- OA status
-
greenOpen access status per OpenAlex
- OA URL
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https://www.biorxiv.org/content/biorxiv/early/2024/11/30/2024.11.29.625993.full.pdfDirect OA link when available
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Biogenesis, Terminal (telecommunication), Differential (mechanical device), Cell biology, Neuroscience, Pathology, Biology, Chemistry, Medicine, Computer science, Physics, Biochemistry, Gene, Thermodynamics, TelecommunicationsTop concepts (fields/topics) attached by OpenAlex
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4Total citation count in OpenAlex
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2025: 4Per-year citation counts (last 5 years)
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133Number of works referenced by this work
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10Other works algorithmically related by OpenAlex
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