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Unraveling amyloid formation paths of Parkinson's disease protein alpha-synuclein triggered by anionic vesicles

Juris Kiskis (Institutionen för biologi och bioteknik, Livsmedelsvetenskap) ; Istvan Horvath (Institutionen för biologi och bioteknik, Kemisk biologi) ; Pernilla Wittung-Stafshede (Institutionen för biologi och bioteknik, Kemisk biologi) ; Sandra Rocha (Institutionen för biologi och bioteknik, Kemisk biologi)
Quarterly Reviews of Biophysics (0033-5835). Vol. 50 (2017), p. 1-9.
[Artikel, refereegranskad vetenskaplig]

Amyloid formation of the synaptic brain protein alpha-synuclein (alpha S) is related to degeneration of dopaminergic neurons in Parkinson's disease patients. aS is thought to function in vesicle transport and fusion and it binds strongly to negatively charged vesicles in vitro. Here we combined circular dichroism, fluorescence and imaging methods in vitro to characterize the interaction of alpha S with negatively charged vesicles of DOPS (1,2-dioleoyl-sn-glycero-3-phospho-L-serine, sodium salt) and DOPG (1,2-dioleoyl-sn-glycero-3-phospho-(1'-rac-glycerol), sodium salt) and the consequences of such interactions on alpha S amyloid formation. We found that lipid head-group chemistry modulates alpha S interactions and also affects amyloid fiber formation. During the course of the experiments, we made the unexpected discovery that pre-formed alpha S oligomers, typically present in a small amount in the alpha S starting material, acted as templates for linear growth of anomalous amyloid fibers in the presence of vesicles. At the same time, the remaining alpha S monomers were restricted from vesicle-mediated nucleation of amyloid fibers. Although not a dominant process in bulk experiments, this hidden alpha S aggregation pathway may be of importance in vivo.

Nyckelord: solution nmr-spectroscopy, phospholipid-binding, lipid vesicles, membrane interactions, packing defects, aggregation, mutation, states, fibrillogenesis, fibrillation

Denna post skapades 2017-04-19. Senast ändrad 2017-10-18.
CPL Pubid: 248897


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