The effect of amino acid substitution in the imperfect repeat sequences of α-synuclein on fibrillation

Ryuichi Harada, Natsuki Kobayashi, Jihoon Kim, Chikashi Nakamura, Sung Woong Han, Kazunori Ikebukuro, Koji Sode

Research output: Contribution to journalArticlepeer-review

15 Citations (Scopus)

Abstract

Human α-synuclein is the causative protein of several neurodegenerative diseases, such as Parkinson's disease (PD) and dementia with Lewy Bodies (DLB). The N-terminal half of α-synuclein contains seven imperfect repeat sequences. One of the PD/DLB-causing point mutations, E46K, has been reported in the imperfect repeat sequences of α-synuclein, and is prone to form amyloid fibrils. The presence of seven imperfect repeats in α-synuclein raises the question of whether or not mutations corresponding to E46K in the other imperfect KTKE(Q)GV repeats have similar effects on aggregation and fibrillation, as well as their propensities to form α-helices. To investigate the effect of E(Q)/K mutations in each imperfect repeat sequence, we substituted the amino acid corresponding to E46K in each of the seven repeated sequences with a Lys residue. The mutations in the imperfect KTKE(Q)GV repeat sequences of the N-terminal region were prone to decrease the lag time of fibril formation. In addition, AFM imaging suggested that the Q24K mutant formed twisted fibrils, while the other mutants formed spherical aggregates and short fibrils. These observations indicate that the effect of the mutations on the kinetics of fibril formation and morphology of fibrils varies according to their location.

Original languageEnglish
Pages (from-to)998-1003
Number of pages6
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1792
Issue number10
DOIs
Publication statusPublished - 2009 Oct

Keywords

  • E46K
  • Fibrillation
  • Imperfect repeat sequences
  • Parkinson's disease
  • α-Synuclein

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology

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