| Abstract | Accumulation of alpha-synuclein resulting in the formation of oligomers and protofibrils has been linked to Parkinson's disease and Lewy body dementia. In contrast, beta-synuclein (beta-syn), a close homologue, does not aggregate and reduces alpha-synuclein (alpha-syn)-related pathology. Although considerable information is available about the conformation of alpha-syn at the initial and end stages of fibrillation, less is known about the dynamic process of alpha-syn conversion to oligomers and how interactions with antiaggregation chaperones such as beta-synuclein might occur. Molecular modeling and molecular dynamics simulations based on the micelle-derived structure of alpha-syn showed that alpha-syn homodimers can adopt nonpropagating (head-to-tail) and propagating (head-to-head) conformations. Propagating alpha-syn dimers on the membrane incorporate additional alpha-syn molecules, leading to the formation of pentamers and hexamers forming a ring-like structure. In contrast, beta-syn dimers do not propagate and block the aggregation of alpha-syn into ring-like oligomers. Under in vitro cell-free conditions, alpha-syn aggregates formed ring-like structures that were disrupted by beta-syn. Similarly, cells expressing alpha-syn displayed increased ion current activity consistent with the formation of Zn(2+)-sensitive nonselective cation channels. These results support the contention that in Parkinson's disease and Lewy body dementia, alpha-syn oligomers on the membrane might form pore-like structures, and that the beneficial effects of beta-synuclein might be related to its ability to block the formation of pore-like structures. |
| Authors | Igor F Tsigelny, Pazit Bar-On, Yuriy Sharikov, Leslie Crews, Makoto Hashimoto, Mark A Miller, Steve H Keller, Oleksandr Platoshyn, Jason X-J Yuan, Eliezer Masliah
(Affiliation: Department of Chemistry, University of California San Diego, La Jolla, CA 92093-0624, USA.)
|
| Journal | The FEBS journal
(FEBS J)
Vol. 274
Issue 7
Pg. 1862-77
(Apr 2007)
ISSN: 1742-464X England |
| PMID | 17381514
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
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| Chemical References |
- Cations
- Ion Channels
- Phosphatidylcholines
- alpha-Synuclein
- beta-Synuclein
- 1-palmitoyl-2-oleoylphosphatidylcholine
- Zinc
|
| Topics |
- Cations
(metabolism)
- Cell Line
- Computer Simulation
- Electrophysiology
- Electrostatics
- Humans
- Ion Channels
(metabolism)
- Microscopy, Electron, Scanning
- Models, Molecular
- Phosphatidylcholines
(chemistry)
- Protein Binding
(drug effects)
- Protein Conformation
- Protein Structure, Quaternary
- Protein Structure, Secondary
- Transfection
- Zinc
(pharmacology)
- alpha-Synuclein
(chemistry, genetics, metabolism)
- beta-Synuclein
(chemistry, genetics, metabolism)
|
