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Sequence Determinants for Amyloid Fibrillogenesis of Human a-Synuclein

journal contribution
posted on 2023-06-08, 07:19 authored by Shahin Zibaee, Ross Jakes, Graham Fraser, Louise SerpellLouise Serpell, R Anthony Crowther, Michel Goedert
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

History

Publication status

  • Published

Journal

Journal of Molecular Biology

ISSN

0022-2836

Issue

2

Volume

374

Page range

454-464

Pages

11.0

Department affiliated with

  • Biochemistry Publications

Full text available

  • No

Peer reviewed?

  • Yes

Legacy Posted Date

2012-02-06

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