Cellular polyamines promote the aggregation of alpha-synuclein.
The cellular polyamines putrescine, spermidine, and spermine accelerate the aggregation and fibrillization of alpha-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 alpha-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 alpha-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, alpha-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 alpha-synuclein to form fibrils and may hence play a role in the formation of cytosolic alpha-synuclein aggregates.
Antony
Thomas
T
Department of Molecular Biology, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, Goettingen D-37077, Germany.
Hoyer
Wolfgang
W
Cherny
Dmitry
D
Heim
Gudrun
G
Jovin
Thomas M
TM
Subramaniam
Vinod
V
D001665:Binding Sites; D002942:Circular Dichroism; D003001:Cloning, Molecular; D004926:Escherichia coli / Q000235:genetics; D006801:Humans; D018625:Microscopy, Atomic Force; D008854:Microscopy, Electron; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000648:ultrastructure*; D010300:Parkinson Disease; D010750:Phosphoproteins / Q000737:chemistry; D011487:Protein Conformation; D011700:Putrescine / Q000502:physiology*; D011994:Recombinant Proteins / Q000737:chemistry; D013050:Spectrometry, Fluorescence; D013095:Spermidine / Q000502:physiology*; D013096:Spermine / Q000502:physiology*; D051843:Synucleins; D051844:alpha-Synuclein
D009419:Nerve Tissue Proteins; D010750:Phosphoproteins; D011994:Recombinant Proteins; C497604:SNCA protein, human; D051843:Synucleins; D051844:alpha-Synuclein; D013096:Spermine; D013095:Spermidine; D011700:Putrescine