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Differential role of C-terminal truncations on alpha-synuclein pathology and Lewy body formation

Mahul-Mellier, Anne Laure ; Altay, Melek Firat ; Maharjan, Niran ; Ait-Bouziad, Nadine ; Chiki, Anass ; Jagannath, Somanath ; Limorenko, Galina LU ; Novello, Salvatore ; Ricci, Jonathan and Jasiqi, Yllza , et al. (2025) In npj Parkinson's Disease 11(1).
Abstract

Alpha-synuclein (aSyn) post-translational modifications (PTM), especially phosphorylation at serine 129 and C-terminal truncations, are highly enriched in Lewy bodies (LB), Lewy neurites, and other pathological aggregates in Parkinson’s disease and synucleinopathies. However, the precise role of these PTM in pathology formation, neurodegeneration, and pathology spreading remains unclear. Here, we systematically investigated the role of post-fibrillization C-terminal aSyn truncations in regulating uptake, processing, seeding, and LB-like inclusion formation using a neuronal seeding model that recapitulates LB formation and neurodegeneration. We show that C-terminal cleavage of aSyn fibrils occurs rapidly post exogenous fibril... (More)

Alpha-synuclein (aSyn) post-translational modifications (PTM), especially phosphorylation at serine 129 and C-terminal truncations, are highly enriched in Lewy bodies (LB), Lewy neurites, and other pathological aggregates in Parkinson’s disease and synucleinopathies. However, the precise role of these PTM in pathology formation, neurodegeneration, and pathology spreading remains unclear. Here, we systematically investigated the role of post-fibrillization C-terminal aSyn truncations in regulating uptake, processing, seeding, and LB-like inclusion formation using a neuronal seeding model that recapitulates LB formation and neurodegeneration. We show that C-terminal cleavage of aSyn fibrils occurs rapidly post exogenous fibril internalization and during intracellular LB-like inclusion formation. Blocking cleavage of internalized fibrils does not affect seeding, but inhibiting enzymes such as calpains 1 and 2 alters LB-like inclusion formation. We show that C-terminal truncations, along with other PTMs, regulate fibril interactome remodeling, shortening, lateral association, and packing. These findings reveal distinct roles of C-terminal truncations at different aggregation stages on the pathway to LB formation, highlighting the need for consideration of stage‑specific strategies to target aSyn proteolytic cleavages.

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publishing date
type
Contribution to journal
publication status
published
subject
in
npj Parkinson's Disease
volume
11
issue
1
article number
261
publisher
Springer Nature
external identifiers
  • pmid:40858624
  • scopus:105014618209
ISSN
2373-8057
DOI
10.1038/s41531-025-01084-y
language
English
LU publication?
yes
id
c3c062c6-a021-4a4a-8f62-56dc33100683
date added to LUP
2025-10-03 08:57:49
date last changed
2025-10-04 03:00:07
@article{c3c062c6-a021-4a4a-8f62-56dc33100683,
  abstract     = {{<p>Alpha-synuclein (aSyn) post-translational modifications (PTM), especially phosphorylation at serine 129 and C-terminal truncations, are highly enriched in Lewy bodies (LB), Lewy neurites, and other pathological aggregates in Parkinson’s disease and synucleinopathies. However, the precise role of these PTM in pathology formation, neurodegeneration, and pathology spreading remains unclear. Here, we systematically investigated the role of post-fibrillization C-terminal aSyn truncations in regulating uptake, processing, seeding, and LB-like inclusion formation using a neuronal seeding model that recapitulates LB formation and neurodegeneration. We show that C-terminal cleavage of aSyn fibrils occurs rapidly post exogenous fibril internalization and during intracellular LB-like inclusion formation. Blocking cleavage of internalized fibrils does not affect seeding, but inhibiting enzymes such as calpains 1 and 2 alters LB-like inclusion formation. We show that C-terminal truncations, along with other PTMs, regulate fibril interactome remodeling, shortening, lateral association, and packing. These findings reveal distinct roles of C-terminal truncations at different aggregation stages on the pathway to LB formation, highlighting the need for consideration of stage‑specific strategies to target aSyn proteolytic cleavages.</p>}},
  author       = {{Mahul-Mellier, Anne Laure and Altay, Melek Firat and Maharjan, Niran and Ait-Bouziad, Nadine and Chiki, Anass and Jagannath, Somanath and Limorenko, Galina and Novello, Salvatore and Ricci, Jonathan and Jasiqi, Yllza and Vingill, Siv and Wade-Martins, Richard and Holton, Janice and Strand, Catherine and Haikal, Caroline and Li, Jia Yi and Hamelin, Romain and Croisier, Marie and Knott, Graham and Mairet-Coello, Georges and Weerens, Laura and Michel, Anne and Downey, Patrick and Citron, Martin and Lashuel, Hilal A.}},
  issn         = {{2373-8057}},
  language     = {{eng}},
  number       = {{1}},
  publisher    = {{Springer Nature}},
  series       = {{npj Parkinson's Disease}},
  title        = {{Differential role of C-terminal truncations on alpha-synuclein pathology and Lewy body formation}},
  url          = {{http://dx.doi.org/10.1038/s41531-025-01084-y}},
  doi          = {{10.1038/s41531-025-01084-y}},
  volume       = {{11}},
  year         = {{2025}},
}