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Small molecules detected by second-harmonic generation modulate the conformation of monomeric α-synuclein and reduce its aggregation in cells

Lookup NU author(s): Professor Tiago Outeiro

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Abstract

© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.Proteins are structurally dynamic molecules that perform specialized functions through unique conformational changes accessible in physiological environments. An ability to specifically and selectively control protein function via conformational modulation is an important goal for development of novel therapeutics and studies of protein mechanism in biological networks and disease. Here we applied a second-harmonic generation-based technique for studying protein conformation in solution and in real time to the intrinsically disordered, Parkinson disease related protein α-synuclein. From a fragment library, we identified small molecule modulators that bind to monomeric α-synuclein in vitro and significantly reduce α-synuclein aggregation in a neuronal cell culture model. Our results indicate that the conformation of α-synuclein is linked to the aggregation of protein in cells. They also provide support for a therapeutic strategy of targeting specific conformations of the protein to suppress or control its aggregation.


Publication metadata

Author(s): Moree B, Yin G, Lazaro DF, Munari F, Strohaker T, Giller K, Becker S, Outeiro TF, Zweckstetter M, Salafsky J

Publication type: Article

Publication status: Published

Journal: Journal of Biological Chemistry

Year: 2015

Volume: 290

Issue: 46

Pages: 27582-27593

Online publication date: 22/09/2015

Acceptance date: 01/01/1900

ISSN (print): 0021-9258

ISSN (electronic): 1083-351X

Publisher: American Society for Biochemistry and Molecular Biology Inc.

URL: https://doi.org10.1074/jbc.M114.636027

DOI: 10.1074/jbc.M114.636027

PubMed id: 26396193


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