Synthesis and Characterization of High Affinity Fluorogenic α-synuclein Probes

Overview

Journal Chem Commun (Camb)

Publisher Royal Society of Chemistry

Specialty Chemistry

Date 2020 Feb 28

PMID 32104795

Citations 12

Authors

Zsofia Lengyel-Zhand

John J Ferrie

Bieneke Janssen

Chia-Ju Hsieh

Thomas Graham

Kui-Ying Xu

Conor M Haney

Virginia M-Y Lee

John Q Trojanowski

E James Petersson

Robert H Mach

Affiliations

Soon will be listed here.

Abstract

Fluorescent small molecules are powerful tools for imaging α-synuclein pathology in vitro and in vivo. In this work, we explore benzofuranone as a potential scaffold for the design of fluorescent α-synuclein probes. These compounds have high affinity for α-synuclein, show fluorescent turn-on upon binding to fibrils, and display different binding to Lewy bodies, Lewy neurites and glial cytoplasmic inclusion pathologies in post-mortem brain tissue. These studies not only reveal the potential of benzofuranone compounds as α-synuclein specific fluorescent probes, but also have implications for the ways in which α-synucleinopathies are conformationally different and display distinct small molecule binding sites.

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References

Maskevich A, Stsiapura V, Kuzmitsky V, Kuznetsova I, Povarova O, Uversky V . Spectral properties of thioflavin T in solvents with different dielectric properties and in a fibril-incorporated form. J Proteome Res. 2007; 6(4):1392-401. DOI: 10.1021/pr0605567. View

Khurana R, Uversky V, Nielsen L, Fink A . Is Congo red an amyloid-specific dye?. J Biol Chem. 2001; 276(25):22715-21. DOI: 10.1074/jbc.M011499200. View

Tu P, Galvin J, Baba M, Giasson B, Tomita T, Leight S . Glial cytoplasmic inclusions in white matter oligodendrocytes of multiple system atrophy brains contain insoluble alpha-synuclein. Ann Neurol. 1998; 44(3):415-22. DOI: 10.1002/ana.410440324. View

Volkova K, Kovalska V, Balanda A, Losytskyy M, Golub A, Vermeij R . Specific fluorescent detection of fibrillar alpha-synuclein using mono- and trimethine cyanine dyes. Bioorg Med Chem. 2007; 16(3):1452-9. DOI: 10.1016/j.bmc.2007.10.051. View

Skovronsky D, Lee V, Trojanowski J . Neurodegenerative diseases: new concepts of pathogenesis and their therapeutic implications. Annu Rev Pathol. 2007; 1:151-70. DOI: 10.1146/annurev.pathol.1.110304.100113. View

Lai H, Ng W, Gentleman S, Wu W . Chemical Probes for Visualizing Intact Animal and Human Brain Tissue. Cell Chem Biol. 2017; 24(6):659-672. DOI: 10.1016/j.chembiol.2017.05.015. View

Celej M, Jares-Erijman E, Jovin T . Fluorescent N-arylaminonaphthalene sulfonate probes for amyloid aggregation of alpha-synuclein. Biophys J. 2008; 94(12):4867-79. PMC: 2397331. DOI: 10.1529/biophysj.107.125211. View

Peng C, Gathagan R, Covell D, Medellin C, Stieber A, Robinson J . Cellular milieu imparts distinct pathological α-synuclein strains in α-synucleinopathies. Nature. 2018; 557(7706):558-563. PMC: 5970994. DOI: 10.1038/s41586-018-0104-4. View

Celej M, Caarls W, Demchenko A, Jovin T . A triple-emission fluorescent probe reveals distinctive amyloid fibrillar polymorphism of wild-type alpha-synuclein and its familial Parkinson's disease mutants. Biochemistry. 2009; 48(31):7465-72. DOI: 10.1021/bi9003843. View

10.

Jun J, Haney C, Karpowicz Jr R, Giannakoulias S, Lee V, Petersson E . A "Clickable" Photoconvertible Small Fluorescent Molecule as a Minimalist Probe for Tracking Individual Biomolecule Complexes. J Am Chem Soc. 2019; 141(5):1893-1897. PMC: 6732186. DOI: 10.1021/jacs.8b13094. View

11.

Reinke A, Seh H, Gestwicki J . A chemical screening approach reveals that indole fluorescence is quenched by pre-fibrillar but not fibrillar amyloid-beta. Bioorg Med Chem Lett. 2009; 19(17):4952-7. PMC: 2730169. DOI: 10.1016/j.bmcl.2009.07.082. View

12.

Sulatskaya A, Rodina N, Sulatsky M, Povarova O, Antifeeva I, Kuznetsova I . Investigation of α-Synuclein Amyloid Fibrils Using the Fluorescent Probe Thioflavin T. Int J Mol Sci. 2018; 19(9). PMC: 6163839. DOI: 10.3390/ijms19092486. View

13.

Nilsson M . Techniques to study amyloid fibril formation in vitro. Methods. 2004; 34(1):151-60. DOI: 10.1016/j.ymeth.2004.03.012. View

14.

Klunk W, Wang Y, Huang G, Debnath M, Holt D, Mathis C . Uncharged thioflavin-T derivatives bind to amyloid-beta protein with high affinity and readily enter the brain. Life Sci. 2001; 69(13):1471-84. DOI: 10.1016/s0024-3205(01)01232-2. View

15.

Covell D, Robinson J, Akhtar R, Grossman M, Weintraub D, Bucklin H . Novel conformation-selective alpha-synuclein antibodies raised against different in vitro fibril forms show distinct patterns of Lewy pathology in Parkinson's disease. Neuropathol Appl Neurobiol. 2017; 43(7):604-620. PMC: 5632188. DOI: 10.1111/nan.12402. View

16.

Guo J, Covell D, Daniels J, Iba M, Stieber A, Zhang B . Distinct α-synuclein strains differentially promote tau inclusions in neurons. Cell. 2013; 154(1):103-17. PMC: 3820001. DOI: 10.1016/j.cell.2013.05.057. View

17.

Lippa C, Fujiwara H, Mann D, Giasson B, Baba M, Schmidt M . Lewy bodies contain altered alpha-synuclein in brains of many familial Alzheimer's disease patients with mutations in presenilin and amyloid precursor protein genes. Am J Pathol. 1998; 153(5):1365-70. PMC: 1853391. DOI: 10.1016/s0002-9440(10)65722-7. View

18.

Xue C, Lin T, Chang D, Guo Z . Thioflavin T as an amyloid dye: fibril quantification, optimal concentration and effect on aggregation. R Soc Open Sci. 2017; 4(1):160696. PMC: 5319338. DOI: 10.1098/rsos.160696. View

19.

Chu W, Zhou D, Gaba V, Liu J, Li S, Peng X . Design, Synthesis, and Characterization of 3-(Benzylidene)indolin-2-one Derivatives as Ligands for α-Synuclein Fibrils. J Med Chem. 2015; 58(15):6002-17. PMC: 4624220. DOI: 10.1021/acs.jmedchem.5b00571. View

20.

Morris G, Huey R, Lindstrom W, Sanner M, Belew R, Goodsell D . AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J Comput Chem. 2009; 30(16):2785-91. PMC: 2760638. DOI: 10.1002/jcc.21256. View