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  Dependence of α-synuclein aggregate morphology on solution conditions

Hoyer, W., Antony, T., Cherny, D. I., Heim, G., Jovin, T. M., & Subramaniam, V. (2002). Dependence of α-synuclein aggregate morphology on solution conditions. Journal of Molecular Biology, 322(2), 383-393. Retrieved from http://www.sciencedirect.com/science?_ob=MImg&_imagekey=B6WK7-46P40TK-F-1&_cdi=6899&_user=38661&_pii=S0022283602007751&_origin=search&_coverDate=09%2F13%2F2002&_sk=996779997&view=c&wchp=dGLbVlW-zSkzk&md5=bd81ff0670bdc1eb0a0858e2cc7bcf74&ie=/sdarticle.pdf.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0012-F2F8-C Version Permalink: http://hdl.handle.net/11858/00-001M-0000-002A-39E1-9
Genre: Journal Article

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 Creators:
Hoyer, W.1, Author              
Antony, T.1, Author              
Cherny, D. I.1, Author              
Heim, G.2, Author              
Jovin, T. M.1, Author              
Subramaniam, V.1, Author              
Affiliations:
1Department of Molecular Biology, MPI for biophysical chemistry, Max Planck Society, ou_578628              
2Facility for Electron Microscopy, MPI for biophysical chemistry, Max Planck Society, ou_578615              

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Free keywords: α-synuclein; thioflavin-T; protein aggregation; electron microscopy; scanning force microscopy
 Abstract: 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.

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Language(s): eng - English
 Dates: 2004-08-042002-09-13
 Publication Status: Published in print
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 Rev. Method: Peer
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Title: Journal of Molecular Biology
Source Genre: Journal
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Pages: - Volume / Issue: 322 (2) Sequence Number: - Start / End Page: 383 - 393 Identifier: -