Sequence Determinants for Amyloid Fibrillogenesis of Human a-Synuclein

Zibaee, Shahin, Jakes, Ross, Fraser, Graham, Serpell, Louise C, Crowther, R Anthony and Goedert, Michel (2007) Sequence Determinants for Amyloid Fibrillogenesis of Human a-Synuclein. Journal of Molecular Biology, 374 (2). pp. 454-464. ISSN 0022-2836

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Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are characterized by the presence of filamentous inclusions in nerve cells. These filaments are amyloid fibrils that are made of the protein a-synuclein, which is genetically linked to rare cases of PD and DLB. ß-Synuclein, which shares 60% identity with a-synuclein, is not found in the inclusions. Furthermore, while recombinant a-synuclein readily assembles into amyloid fibrils, ß-synuclein fails to do so. It has been suggested that this may be due to the lack in ß-synuclein of a hydrophobic region that spans residues 73¿83 of a-synuclein. Here, fibril assembly of recombinant human a-synuclein, a-synuclein deletion mutants, ß-synuclein and ß/a-synuclein chimeras was assayed quantitatively by thioflavin T fluorescence and semi-quantitatively by transmission electron microscopy. Deletion of residues 73¿83 from a-synuclein did not abolish filament formation. Furthermore, a chimera of ß-synuclein with a-synuclein(73¿83) inserted was significantly less fibrillogenic than wild-type a-synuclein. These findings, together with results obtained using a number of recombinant synucleins, showed a correlation between fibrillogenesis and mean ß-strand propensity, hydrophilicity and charge of the amino acid sequences. The combination of these simple physicochemical properties with a previously described calculation of ß-strand contiguity allowed us to design mutations that changed the fibrillogenic propensity of a-synuclein in predictable ways

Item Type: Article
Schools and Departments: School of Life Sciences > Biochemistry
Depositing User: Louise Serpell
Date Deposited: 06 Feb 2012 20:41
Last Modified: 22 Mar 2012 14:48
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