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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Abstract

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
URI: http://sro.sussex.ac.uk/id/eprint/27435
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