TAILIEUCHUNG - Báo cáo khoa học: Dynamics of a-synuclein aggregation and inhibition of pore-like oligomer development by b-synuclein

Accumulation ofa-synuclein resulting in the formation of oligomers and protofibrils has been linked to Parkinson’s disease and Lewy body demen-tia. In contrast, b-synuclein (b-syn), a close homologue, does not aggregate and reducesa-synuclein (a-syn)-related pathology. | ễFEBS Journal Dynamics of a-synuclein aggregation and inhibition of pore-like oligomer development by b-synuclein Igor F. Tsigelny1 2 Pazit Bar-On3 Yuriy Sharikov2 Leslie Crews4 Makoto Hashimoto3 Mark A. Miller2 Steve H. Keller5 Oleksandr Platoshyn5 Jason . Yuan5 and Eliezer Masliah3 4 1 Departments of Chemistry and Biochemistry University of California San Diego La Jolla CA USA 2 San Diego Super Computer Center University of California San Diego La Jolla CA USA 3 Department of Neurosciences University of California San Diego La Jolla CA USA 4 Department of Pathology University of California San Diego La Jolla CA USA 5 Department of Medicine University of California San Diego La Jolla CA USA Keywords cation channels modeling molecular dynamics oligomers synuclein Correspondence E. Masliah Department of Neurosciences University of California San Diego La Jolla CA 92093-0624 USA Fax 1 858 5346232 Tel 1 858 5348992 E-mail emasliah@ Received 1 December 2006 revised 26 January 2007 accepted 8 February 2007 doi Accumulation of a-synuclein resulting in the formation of oligomers and protofibrils has been linked to Parkinson s disease and Lewy body dementia. In contrast p-synuclein p-syn a close homologue does not aggregate and reduces a-synuclein a-syn -related pathology. Although considerable information is available about the conformation of a-syn at the initial and end stages of fibrillation less is known about the dynamic process of a-syn conversion to oligomers and how interactions with antiaggregation chaperones such as p-synuclein might occur. Molecular modeling and molecular dynamics simulations based on the micelle-derived structure of a-syn showed that a-syn homodimers can adopt nonpropagating head-to-tail and propagating head-to-head conformations. Propagating a-syn dimers on the membrane incorporate additional a-syn molecules leading to the formation of pentamers and hexamers forming a ring-like structure. In .

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