Parkinson's disease-associated alpha-synuclein is more fibrillogenic than beta- and gamma-synuclein and cannot cross-seed its homologs.
Parkinson's disease (PD) is a neurodegenerative disorder that is pathologically characterized by the presence of intracytoplasmic Lewy bodies. Recently, two point mutations in alpha-synuclein were found to be associated with familial PD, but as of yet no mutations have been described in the homologous genes beta- and gamma-synuclein. alpha-Synuclein forms the major fibrillar component of Lewy bodies, but these do not stain for beta- or gamma-synuclein. This result is very surprising, given the extent of sequence conservation and the high similarity in expression and subcellular localization, in particular between alpha- and beta-synuclein. Here we compare in vitro fibrillogenesis of all three purified synucleins. We show that fresh solutions of alpha-, beta-, and gamma- synuclein show the same natively unfolded structure. While over time alpha-synuclein forms the previously described fibrils, no fibrils could be detected for beta- and gamma-synuclein under the same conditions. Most importantly, beta- and gamma-synuclein could not be cross-seeded with alpha-synuclein fibrils. However, under conditions that drastically accelerate aggregation, gamma-synuclein can form fibrils with a lag phase roughly three times longer than alpha-synuclein. These results indicate that beta- and gamma-synuclein are intrinsically less fibrillogenic than alpha-synuclein and cannot form mixed fibrils with alpha-synuclein, which may explain why they do not appear in the pathological hallmarks of PD, although they are closely related to alpha-synuclein and are also abundant in brain.
Biere
A L
AL
Amgen, Inc., Thousand Oaks, California 91320-1789, USA. abiere@amgen.com
Wood
S J
SJ
Wypych
J
J
Steavenson
S
S
Jiang
Y
Y
Anafi
D
D
Jacobsen
F W
FW
Jarosinski
M A
MA
Wu
G M
GM
Louis
J C
JC
Martin
F
F
Narhi
L O
LO
Citron
M
M
D000595:Amino Acid Sequence; D001483:Base Sequence; D002942:Circular Dichroism; D017931:DNA Primers; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000378:metabolism; D010300:Parkinson Disease / Q000378:metabolism*; D017510:Protein Folding; D017386:Sequence Homology, Amino Acid; D013057:Spectrum Analysis / Q000379:methods; D051843:Synucleins; D051844:alpha-Synuclein; D051846:beta-Synuclein; D051845:gamma-Synuclein
D017931:DNA Primers; D009419:Nerve Tissue Proteins; D051843:Synucleins; D051844:alpha-Synuclein; D051846:beta-Synuclein; D051845:gamma-Synuclein