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Extrinsic Amyloid-Binding Dyes for Detection of Individual Protein Aggregates in Solution.

Artikel i vetenskaplig tidskrift
Författare Christopher G Taylor
Georg Meisl
Mathew H Horrocks
Henrik Zetterberg
Tuomas P J Knowles
David Klenerman
Publicerad i Analytical chemistry
Volym 90
Nummer/häfte 17
Sidor 10385–10393
ISSN 1520-6882
Publiceringsår 2018
Publicerad vid Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi
Sidor 10385–10393
Språk en
Länkar dx.doi.org/10.1021/acs.analchem.8b0...
www.ncbi.nlm.nih.gov/entrez/query.f...
Ämneskategorier Neurokemi

Sammanfattning

Protein aggregation is a key molecular feature underlying a wide array of neurodegenerative disorders, including Alzheimer's and Parkinson's diseases. To understand protein aggregation in molecular detail, it is crucial to be able to characterize the array of heterogeneous aggregates that are formed during the aggregation process. We present here a high-throughput method to detect single protein aggregates, in solution, from a label-free aggregation reaction, and we demonstrate the approach with the protein associated with Parkinson's disease, α-synuclein. The method combines single-molecule confocal microscopy with a range of amyloid-binding extrinsic dyes, including thioflavin T and pentameric formylthiophene acetic acid, and we show that we can observe aggregates at low picomolar concentrations. The detection of individual aggregates allows us to quantify their numbers. Furthermore, we show that this approach also allows us to gain structural insights from the emission intensity of the extrinsic dyes that are bound to aggregates. By analyzing the time evolution of the aggregate populations on a single-molecule level, we then estimate the fragmentation rate of aggregates, a key process that underlies the multiplication of pathological aggregates. We additionally demonstrate that the method permits the detection of these aggregates in biological samples. The capability to detect individual protein aggregates in solution opens up a range of new applications, including exploiting the potential of this method for high-throughput screening of human biofluids for disease diagnosis and early detection.

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