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Differential role of C-terminal truncations on alpha-synuclein pathology and Lewy body formation
Anne‐Laure Mahul‐Mellier, Melek Firat Altay, Niran Maharjan, Nadine Ait‐Bouziad, Anass Chiki, Somanath Jagannath, Galina Limorenko, Salvatore Novello et al.. npj Parkinson s Disease, 2025-08-26
Topic: Brain proteins, microglia and lab models
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.
Key findings
- 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.
Why it matters
In a neuronal cell model, cutting off the tail end of alpha-synuclein protein at different stages affected how Lewy body-like clumps formed, and blocking certain enzymes changed this process. The authors say stage-specific strategies may be needed to target these protein cleavages, but this is laboratory work, not a treatment.
Study details
- Evidence strengthLow
How this study scored 46/100
Published in a peer-reviewed journal. Scored zero for study design, sample size, effect reported, studied in people and randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (npj Parkinson s Disease) |
| Journal's citation record | 1 / 4 | Npj Parkinson s Disease: journal h-index 87 (OpenAlex, 2026-10-29) |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 4 / 5 | 2025 — within 3 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 3 / 7 | Cited 17 times (OpenAlex, 2026-10-10) |
| Citations per year | 2 / 5 | 5.7 citations a year over 3 year(s) since 2025 |
| Impact for its field and year | 4 / 6 | Cited 9.6× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 0 / 6 | No other study in this library cites it |
| Still being cited | 2 / 4 | Cited 17 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 3 / 4 | Last-listed author Hilal Ahmed Lashuel: h-index 92 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | University of Oxford: institution h-index 2,205 (OpenAlex) |
| Multi-centre collaboration | 3 / 3 | OpenAlex lists 12 institution(s) in 7 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 40858624) |
| Free to read | 2 / 2 | Free to read |
| Total | 46 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
- DOI: 10.1038/s41531-025-01084-y
- PubMed: 40858624
- Original source →
- Free full text: npj Parkinson s Disease →
Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. The record's author list ends in “et al.”, so not every author is named. Check the citation against the original before you use it.
APA 7th
Mahul‐Mellier, A., Altay, M. F., Maharjan, N., Ait‐Bouziad, N., Chiki, A., Jagannath, S., et al. (2025). Differential role of C-terminal truncations on alpha-synuclein pathology and Lewy body formation. npj Parkinson s Disease. https://doi.org/10.1038/s41531-025-01084-y
Vancouver
Mahul‐Mellier A, Altay MF, Maharjan N, Ait‐Bouziad N, Chiki A, Jagannath S, et al. Differential role of C-terminal truncations on alpha-synuclein pathology and Lewy body formation. npj Parkinson s Disease. 2025. doi:10.1038/s41531-025-01084-y. PMID: 40858624.
BibTeX
@article{mahulmellier2025-40858624,
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 others},
title = {{Differential role of C-terminal truncations on alpha-synuclein pathology and Lewy body formation}},
journal = {npj Parkinson s Disease},
year = {2025},
doi = {10.1038/s41531-025-01084-y},
pmid = {40858624},
url = {https://doi.org/10.1038/s41531-025-01084-y}
}
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