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Abstract

The cellular polyamines putrescine, spermidine, and spermine accelerate the aggregation and fibrillization of α-synuclein, the major protein component of Lewy bodies associated with Parkinson's disease. Circular dichroism and fluorometric thioflavin T kinetic studies showed a transition of α-synuclein from unaggregated to highly aggregated states, characterized by lag and transition phases. In the presence of polyamines, both the lag and transition times were significantly shorter. All three polyamines accelerated the aggregation and fibrillization of α-synuclein to a degree that increased with the total charge, length, and concentration of the polyamine. Electron and scanning force microscopy of the reaction products after the lag phase revealed the presence of aggregated particles (protofibrils) and small fibrils. At the end of the transition phase, α-synuclein formed long fibrils in all cases, although some morphological variations were apparent. In the presence of polyamines, fibrils formed large networks leading ultimately to condensed aggregates. In the absence of polyamines, fibrils were mostly isolated. We conclude that the polyamines at physiological concentrations can modulate the propensity of α-synuclein to form fibrils and may hence play a role in the formation of cytosolic alpha- synuclein aggregates.