Conformational Behavior of Human α-synuclein is Modulated by Familial Parkinson’s Disease Point Mutations A30P and A53T

Document Type


Publication Date



Parkinson’s Disease, α-synuclein, Familial Parkinson’s Disease Point Mutations, Partially-folded Intermediate, Aggregation, Fibrillation, Heparin, Pesticides

Digital Object Identifier (DOI)



Structural properties and response to changes in the environment of wild-type (WT), A30P and A53T α-synucleins, as well as their propensity to aggregate or form fibrils, were compared by a variety of biophysical methods, including far-UV CD, FTIR, SAXS, static light scattering and Thioflavin T (TFT) fluorescence. All three proteins were natively unfolded under physiological conditions but adopted identical partially-folded conformations under conditions of acidic pH or high temperature. The initial kinetic event in the fibrillation of all three α-synucleins was shown to be the formation of a partially-folded intermediate with properties close to those described for these proteins at acidic pH or at high temperatures. Both mutants showed a greater propensity to form non-fibrillar aggregates than wild-type protein. All three proteins formed fibrils faster in the presence of heparin, although substantially higher concentrations were required for the A30P mutant. In contrast to the wild-type and A53T proteins, in which fibrillation was further accelerated by the presence of the pesticide diethyldithiocarbamate (DDC), the A30P mutant was inhibited by DDC. The mutant proteins had significantly lower affinity for DDC than the WT. A model of the effect of mutations on the aggregation behavior of α-synuclein is proposed, which explains the different effects of exogenous agents on the three proteins, based on different kinetic partitioning along pathways leading to fibrils and to non-fibrillar aggregates.

Was this content written or created while at USF?


Citation / Publisher Attribution

NeuroToxicology, v. 23, issue 4-5, p. 553-567