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alpha-synuclein fibrillogenesis is nucleation-dependent. Implications for the pathogenesis of Parkinson's disease
Wood SJ, Wypych J, Steavenson S, Louis JC, Citron M, Biere AL.. The Journal of biological chemistry, 1999-07-01
Topic: Brain proteins, microglia and lab models
Parkinson's disease (PD) is a neurodegenerative disorder that is pathologically characterized by the presence of intracytoplasmic Lewy bodies, the major components of which are filaments consisting of alpha-synuclein. Two recently identified point mutations in alpha-synuclein are the only known genetic causes of PD. alpha-Synuclein fibrils similar to the Lewy body filaments can be formed in vitro, and we have shown recently that both PD-linked mutations accelerate their formation. This study addresses the mechanism of alpha-synuclein aggregation: we show that (i) it is a nucleation-dependent process that can be seeded by aggregated alpha-synuclein functioning as nuclei, (ii) this fibril growth follows first-order kinetics with respect to alpha-synuclein concentration, and (iii) mutant alpha-synuclein can seed the aggregation of wild type alpha-synuclein, which leads us to predict that the Lewy bodies of familial PD patients with alpha-synuclein mutations will contain both, the mutant and the wild type protein. Finally (iv), we show that wild type and mutant forms of alpha-synuclein do not differ in their critical concentrations. These results suggest that differences in aggregation kinetics of alpha-synucleins cannot be explained by differences in solubility but are due to different nucleation rates. Consequently, alpha-synuclein nucleation may be the rate-limiting step for the formation of Lewy body alpha-synuclein fibrils in Parkinson's disease.
Key findings
- These results suggest that differences in aggregation kinetics of alpha-synucleins cannot be explained by differences in solubility but are due to different nucleation rates.
Why it matters
Alpha-synuclein fibril formation is nucleation-dependent and can be seeded by aggregated alpha-synuclein, with mutant forms able to seed wild-type protein. This is in-vitro Parkinson's disease chemistry with no treatment tested.
Study details
- Evidence strengthLow
How this study scored 45/100
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 (The Journal of biological chemistry) |
| Journal's citation record | 4 / 4 | Journal of Biological Chemistry: journal h-index 780 (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 | 1 / 5 | 1999 — older than 20 years, still counted |
| 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 | 6 / 7 | Cited 722 times (OpenAlex, 2026-10-10) |
| Citations per year | 4 / 5 | 24.9 citations a year over 29 year(s) since 1999 |
| Impact for its field and year | 4 / 6 | Cited 19.7× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 2 / 6 | Cited by 6 other studies in this library |
| Still being cited | 2 / 4 | Cited 48 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 1 / 4 | Last-listed author Anja Leona Biere: h-index 12 (OpenAlex, whole career) |
| Institution's track record | 1 / 3 | Amgen (United States): institution h-index 779 (OpenAlex) |
| Multi-centre collaboration | 0 / 3 | OpenAlex lists 1 institution(s) in 1 country — scores zero (affiliation lists can be incomplete) |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 10391881) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Total | 45 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
- DOI: 10.1074/jbc.274.28.19509
- PubMed: 10391881
- Original source →
- Free full text: Journal of Biological Chemistry →
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. Check the citation against the original before you use it.
APA 7th
Wood, S. J., Wypych, J., Steavenson, S., Louis, J. C., Citron, M., & Biere, A. L. (1999). alpha-synuclein fibrillogenesis is nucleation-dependent. Implications for the pathogenesis of Parkinson's disease. The Journal of biological chemistry. https://doi.org/10.1074/jbc.274.28.19509
Vancouver
Wood SJ, Wypych J, Steavenson S, Louis JC, Citron M, Biere AL. alpha-synuclein fibrillogenesis is nucleation-dependent. Implications for the pathogenesis of Parkinson's disease. The Journal of biological chemistry. 1999. doi:10.1074/jbc.274.28.19509. PMID: 10391881.
BibTeX
@article{wood1999-10391881,
author = {Wood, S. J. and Wypych, J. and Steavenson, S. and Louis, J. C. and Citron, M. and Biere, A. L.},
title = {{alpha-synuclein fibrillogenesis is nucleation-dependent. Implications for the pathogenesis of Parkinson's disease}},
journal = {The Journal of biological chemistry},
year = {1999},
doi = {10.1074/jbc.274.28.19509},
pmid = {10391881},
url = {https://doi.org/10.1074/jbc.274.28.19509}
}
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