Both familial Parkinson's disease mutations accelerate alpha-synuclein aggregation.
Parkinson's disease (PD) is a neurodegenerative disorder that is pathologically characterized by the presence of intracytoplasmic Lewy bodies, the major component of which are filaments consisting of alpha-synuclein. Two recently identified point mutations in alpha-synuclein are the only known genetic causes of PD, but their pathogenic mechanism is not understood. Here we show that both wild type and mutant alpha-synuclein form insoluble fibrillar aggregates with antiparallel beta-sheet structure upon incubation at physiological temperature in vitro. Importantly, aggregate formation is accelerated by both PD-linked mutations. Under the experimental conditions, the lag time for the formation of precipitable aggregates is about 280 h for the wild type protein, 180 h for the A30P mutant, and only 100 h for the A53T mutant protein. These data suggest that the formation of alpha-synuclein aggregates could be a critical step in PD pathogenesis, which is accelerated by the PD-linked mutations.
Narhi
L
L
Amgen, Inc., Thousand Oaks, California 91320-1789, USA.
Wood
S J
SJ
Steavenson
S
S
Jiang
Y
Y
Wu
G M
GM
Anafi
D
D
Kaufman
S A
SA
Martin
F
F
Sitney
K
K
Denis
P
P
Louis
J C
JC
Wypych
J
J
Biere
A L
AL
Citron
M
M
D002460:Cell Line; D002942:Circular Dichroism; D003001:Cloning, Molecular; D006801:Humans; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000235:genetics*; D010300:Parkinson Disease / Q000235:genetics*; D010750:Phosphoproteins / Q000737:chemistry* / Q000235:genetics*; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D017550:Spectroscopy, Fourier Transform Infrared; D051843:Synucleins; D051844:alpha-Synuclein
D009419:Nerve Tissue Proteins; D010750:Phosphoproteins; C497604:SNCA protein, human; D051843:Synucleins; D051844:alpha-Synuclein