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ID: 16663.0, MPI für biophysikalische Chemie / Molekulare Biologie (Dr. Thomas M. Jovin)
Dependence of α-synuclein aggregate morphology on solution conditions
Authors:Hoyer, W.; Antony, T.; Cherny, D. I.; Heim, G.; Jovin, T. M.; Subramaniam, V.
Date of Publication (YYYY-MM-DD):2002-09-13
Title of Journal:Journal of Molecular Biology
Issue / Number:2
Start Page:383
End Page:393
Review Status:Peer-review
Audience:Not Specified
Abstract / Description:α-Synuclein is the major component of Lewy bodies and Lewy neurites, which are granular and filamentous protein inclusions that are the defining pathological features of several neurodegenerative conditions such as Parkinson's disease. Fibrillar aggregates formed from α-synuclein in vitro resemble brain-derived material, but the role of such aggregates in the etiology of Parkinson's disease and their relation to the toxic molecular species remain unclear. In this study, we investigated the effects of pH and salt concentration on the in vitro assembly of human wild-type α-synuclein, particularly with regard to aggregation rate and aggregate morphology. Aggregates formed at pH 7.0 and pH 6.0 in the absence of NaCl and MgCl, were fibrillar; the pH 6.0 fibrils displayed a helical twist, as clearly evident by scanning force and electron microscopy. Incubations at pH 7.0 remained transparent during the process of aggregation and exhibited strong thioflavin-T and weak 8-anilino-1-naphthalene-sulfonate (ANS) binding; furthermore, they were efficient in seeding fibrillization of fresh solutions. In contrast, incubating α-synuclein at low pH (pH 4.0 or pH 5.0) resulted in the rapid formation of turbid suspensions characterized by strong ANS binding, reduced thioflavin-T binding and reduced seeding efficiency. At pH 4.0, fibril formation was abrogated; instead, very large aggregates (dimensions similar to100 mum) of amorphous appearance were visible by light microscopy. As with acidic conditions, addition of 0.2 M NaCl or 10 mM MgCl, to pH 7.0 incubations led to a shorter aggregation lag time and formation of large, amorphous aggregates. These results demonstrate that the morphology of α-synuclein aggregates is highly sensitive to solution conditions, implying that the fibrillar state does not necessarily represent the predominant or most functionally significant aggregated state under physiological conditions. (C) 2002 Elsevier Science Ltd. All rights reserved.
Free Keywords:α-synuclein; thioflavin-T; protein aggregation; electron microscopy; scanning force microscopy
Comment of the Author/Creator:Date: 2002, SEP 13
Last Change of the Resource (YYYY-MM-DD):2004-08-04
External Publication Status:published
Document Type:Article
Communicated by:N. N.
Affiliations:MPI für biophysikalische Chemie/Abt. Thomas Jovin / 060
External Affiliations:Russian Acad Sci, Inst Genet Mol, Moscow, Russia
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