Parkinson's Disease-associated α-Synuclein Is More Fibrillogenic than β- and γ-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 α-synuclein were found to be associated with familial PD, but as of yet no mutations have been described in the homolog...

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Published in:The Journal of biological chemistry 2000-11, Vol.275 (44), p.34574-34579
Main Authors: Biere, Anja Leona, Wood, Stephen J., Wypych, Jette, Steavenson, Shirley, Jiang, Yijia, Anafi, Dan, Jacobsen, Frederick W., Jarosinski, Mark A., Wu, Gay-May, Louis, Jean-Claude, Martin, Francis, Narhi, Linda O., Citron, Martin
Format: Article
Language:English
Subjects:
a-synuclein
alpha-Synuclein
Amino Acid Sequence
Base Sequence
beta-Synuclein
Circular Dichroism
DNA Primers
gamma-Synuclein
Molecular Sequence Data
Nerve Tissue Proteins - chemistry
Nerve Tissue Proteins - metabolism
Parkinson Disease - metabolism
Protein Folding
Sequence Homology, Amino Acid
Spectrum Analysis - methods
Synucleins
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Summary:Parkinson's disease (PD) is a neurodegenerative disorder that is pathologically characterized by the presence of intracytoplasmic Lewy bodies. Recently, two point mutations in α-synuclein were found to be associated with familial PD, but as of yet no mutations have been described in the homologous genes β- and γ-synuclein. α-Synuclein forms the major fibrillar component of Lewy bodies, but these do not stain for β- or γ-synuclein. This result is very surprising, given the extent of sequence conservation and the high similarity in expression and subcellular localization, in particular between α- and β-synuclein. Here we compare in vitro fibrillogenesis of all three purified synucleins. We show that fresh solutions of α-, β-, and γ- synuclein show the same natively unfolded structure. While over time α-synuclein forms the previously described fibrils, no fibrils could be detected for β- and γ-synuclein under the same conditions. Most importantly, β- and γ-synuclein could not be cross-seeded with α-synuclein fibrils. However, under conditions that drastically accelerate aggregation, γ-synuclein can form fibrils with a lag phase roughly three times longer than α-synuclein. These results indicate that β- and γ-synuclein are intrinsically less fibrillogenic than α-synuclein and cannot form mixed fibrils with α-synuclein, which may explain why they do not appear in the pathological hallmarks of PD, although they are closely related to α-synuclein and are also abundant in brain.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M005514200