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- Title
Dynamics of α-synuclein aggregation and inhibition of pore-like oligomer development by β-synuclein.
- Authors
Tsigelny, Igor F.; Bar-On, Pazit; Sharikov, Yuriy; Crews, Leslie; Hashimoto, Makoto; Miller, Mark A.; Keller, Steve H.; Platoshyn, Oleksandr; Yuan, Jason X.-J.; Masliah, Eliezer
- Abstract
Accumulation of α-synuclein resulting in the formation of oligomers and protofibrils has been linked to Parkinson's disease and Lewy body dementia. In contrast, β-synuclein (β-syn), a close homologue, does not aggregate and reduces α-synuclein (α-syn)-related pathology. Although considerable information is available about the conformation of α-syn at the initial and end stages of fibrillation, less is known about the dynamic process of α-syn conversion to oligomers and how interactions with antiaggregation chaperones such as β-synuclein might occur. Molecular modeling and molecular dynamics simulations based on the micelle-derived structure of α-syn showed that α-syn homodimers can adopt nonpropagating (head-to-tail) and propagating (head-to-head) conformations. Propagating α-syn dimers on the membrane incorporate additional α-syn molecules, leading to the formation of pentamers and hexamers forming a ring-like structure. In contrast, β-syn dimers do not propagate and block the aggregation of α-syn into ring-like oligomers. Under in vitro cell-free conditions, α-syn aggregates formed ring-like structures that were disrupted by β-syn. Similarly, cells expressing α-syn displayed increased ion current activity consistent with the formation of Zn2+-sensitive nonselective cation channels. These results support the contention that in Parkinson's disease and Lewy body dementia, α-syn oligomers on the membrane might form pore-like structures, and that the beneficial effects of β-synuclein might be related to its ability to block the formation of pore-like structures.
- Subjects
CELL aggregation; MOLECULAR dynamics; PARKINSON'S disease; LEWY body dementia; NERVE tissue proteins; CATIONS; OLIGOMERS; MODELING (Sculpture)
- Publication
FEBS Journal, 2007, Vol 274, Issue 7, p1862
- ISSN
1742-464X
- Publication type
Article
- DOI
10.1111/j.1742-4658.2007.05733.x