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Biochem Biophys Res Commun. 2005 Sep 23;335(2):432-6.

Engineered alpha-synuclein prevents wild type and familial Parkin variant fibril formation.

Author information

1
Department of Biotechnology, Faculty of Technology, Tokyo University of Agriculture and Technology, 2-24-16 Naka-cho, 184-8588 Tokyo, Koganei, Japan. sode@cc.tuat.ac.jp

Abstract

Alpha-synuclein is a major component of several pathological lesions diagnostic of specific neurodegenerative disease such as Parkinson's disease. This study focuses on the non-amyloid beta component of Alzheimer's disease amyloid, a key region for the aggregation and fibril formation of alpha-synuclein. Several mutations were introduced in an attempt to repress beta-strand formation and hydrophobic interaction-based aggregation. Although reducing the hydrophobicity drastically decreased fibril formation, the Val70Thr and Val70Pro mutations resulted in an unstable secondary structure thereby increasing non-structural aggregation, instead of fibril formation. Therefore, the stabilization of non-structural natively unfolded status is important to prevent alpha-synuclein fibril formation. Mixing the Val70Thr/Val71Thr double mutant, which has inherently low potential, with the fibril forming alpha-synucleins, WT and Ala53Thr, greatly reduced their fibril formation and aggregation. This double mutant has great potential for further therapeutic approaches.

PMID:
16081040
DOI:
10.1016/j.bbrc.2005.07.100
[Indexed for MEDLINE]

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