title: Both familial Parkinson's disease mutations accelerate alpha-synuclein aggregation.
abstract: 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.
authors: Amgen, Inc., Thousand Oaks, California 91320-1789, USA.
authors: L
authors: L
authors: Narhi
authors: S J
authors: SJ
authors: Wood
authors: S
authors: S
authors: Steavenson
authors: Y
authors: Y
authors: Jiang
authors: G M
authors: GM
authors: Wu
authors: D
authors: D
authors: Anafi
authors: S A
authors: SA
authors: Kaufman
authors: F
authors: F
authors: Martin
authors: K
authors: K
authors: Sitney
authors: P
authors: P
authors: Denis
authors: J C
authors: JC
authors: Louis
authors: J
authors: J
authors: Wypych
authors: A L
authors: AL
authors: Biere
authors: M
authors: M
authors: Citron
mesh_terms: 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
chemical_list: D009419:Nerve Tissue Proteins; D010750:Phosphoproteins; C497604:SNCA protein, human; D051843:Synucleins; D051844:alpha-Synuclein