Effect of melatonin on α-synuclein self-assembly and cytotoxicity

Abstract α-Synuclein (αS) assembly has been implicated as a critical step in the development of Lewy body diseases such as Parkinson's disease and dementia with Lewy bodies. Melatonin (Mel), a secretory product of the pineal gland, is known to have beneficial effects such as an antioxidant func...

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Bibliographic Details
Published in:Neurobiology of aging 2012-09, Vol.33 (9), p.2172-2185
Main Authors: Ono, Kenjiro, Mochizuki, Hideki, Ikeda, Tokuhei, Nihira, Tomoko, Takasaki, Jun-ichi, Teplow, David B, Yamada, Masahito
Format: Article
Language:English
Subjects:
alpha-Synuclein - metabolism
Analysis of Variance
Animals
Antioxidants - pharmacology
Antiparkinson Agents - pharmacology
Brain - cytology
Cells, Cultured
Cytotoxicity
Dementia with Lewy bodies
Dose-Response Relationship, Drug
Embryo, Mammalian
Internal Medicine
Melatonin
Melatonin - pharmacology
Mice
Mice, Inbred C57BL
Microscopy, Electron, Transmission
Neurology
Neurons - drug effects
Neurons - metabolism
Neurons - ultrastructure
Oligomers
Parkinson's disease
Protein Structure, Secondary
Sincalide - pharmacology
Thiazoles - metabolism
Time Factors
Trihexyphenidyl - pharmacology
α-synuclein
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Summary:Abstract α-Synuclein (αS) assembly has been implicated as a critical step in the development of Lewy body diseases such as Parkinson's disease and dementia with Lewy bodies. Melatonin (Mel), a secretory product of the pineal gland, is known to have beneficial effects such as an antioxidant function and neuroprotection. To elucidate whether Mel has an antiassembly effect, here we used circular dichroism spectroscopy, photoinduced crosslinking of unmodified proteins, thioflavin S fluorescence, size exclusion chromatography, electron microscopy and atomic force microscopy to examine the effects of Mel on the αS assembly. We also examined the effects of Mel on αS-induced cytotoxicity by assaying 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide metabolism in αS-treated, primary neuronal cells. Initial studies revealed that Mel blocked αS fibril formation as well as destabilizing preformed αS fibrils. Subsequent evaluation of the assembly-stage specificity of the effect showed that Mel was able to inhibit protofibril formation, oligomerization, and secondary structure transitions. Importantly, Mel decreased αS-induced cytotoxicity. These data suggest a mechanism of action for Mel, inhibition of assembly of toxic polymers and protection of neurons from their effect.
ISSN:0197-4580
1558-1497
DOI:10.1016/j.neurobiolaging.2011.10.015