Dynamics of alpha-synuclein aggregation and inhibition of pore-like oligomer development by beta-synuclein.
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.
Tsigelny
Igor F
IF
Department of Chemistry, University of California San Diego, La Jolla, CA 92093-0624, USA.
Bar-On
Pazit
P
Sharikov
Yuriy
Y
Crews
Leslie
L
Hashimoto
Makoto
M
Miller
Mark A
MA
Keller
Steve H
SH
Platoshyn
Oleksandr
O
Yuan
Jason X-J
JX
Masliah
Eliezer
E
D002412:Cations / Q000378:metabolism; D002460:Cell Line; D003198:Computer Simulation; D004594:Electrophysiology; D006801:Humans; D007473:Ion Channels / Q000378:metabolism; D008855:Microscopy, Electron, Scanning; D008958:Models, Molecular; D010713:Phosphatidylcholines / Q000737:chemistry; D011485:Protein Binding / Q000187:drug effects; D011487:Protein Conformation; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D055672:Static Electricity; D014162:Transfection; D015032:Zinc / Q000494:pharmacology; D051844:alpha-Synuclein / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D051846:beta-Synuclein / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
D002412:Cations; D007473:Ion Channels; D010713:Phosphatidylcholines; D051844:alpha-Synuclein; D051846:beta-Synuclein; D015032:Zinc; C028694:1-palmitoyl-2-oleoylphosphatidylcholine