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Pathobiochemical Effect of Acylated Steryl-β-Glucoside on Aggregation and Cytotoxicity of α-Synuclein

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Abstract

Cycad seed consumption by the native islanders of Guam is frequently associated with high rates of amyotrophic lateral sclerosis-parkinsonism dementia complex (ALS/PDC); furthermore, accompanying pathological examination often exhibits α-synuclein inclusions in the neurons of the affected brain. Acylated steryl-β-glucoside (ASG) contained in cycad seeds is considered as causative environmental risk factor. We aimed to investigate whether ASG influences aggregation and cell toxicity of α-synuclein. To understand whether ASG is a causative factor in the development of ALS/PDC, soybean-derived ASG was tested for its effect on in vitro aggregation of α-synuclein using Thioflavin-T. ASG was also tested to determine whether it modulates α-synuclein cytotoxicity in yeast cells. In addition, we determined whether an interaction between ASG and α-synuclein occurs in the plasma membrane or cytoplasm using three factors: GM1 ganglioside, small unilamellar vesicles, and ATP. In the present study, we found that ASG-mediated acceleration of α-synuclein aggregation is influenced by the presence of ATP, but not by the presence of GM1. ASG accelerated the α-synuclein aggregation in the cytoplasm. ASG also enhanced α-synuclein-induced cytotoxicity in yeast cells. This study demonstrated that ASG directly enhances aggregation and cytotoxicity of α-synuclein, which are often observed in patients with ALS/PDC. These results, using assays that replicate cytoplasmic conditions, are consistent with the molecular mechanism that cytotoxicity is caused by intracellular α-synuclein fibril formation in neuronal cells.

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Acknowledgments

This work was supported by a project grant from NIH project grants (NS 26,994 and NS 11,853) to Robert K. Yu. Thanks are due to Ms. Dawn O’Brien for her editorial assistance.

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Authors and Affiliations

  1. Institute of Molecular Medicine and Genetics, Georgia Health Sciences University, Augusta, GA, 30912, USA

    Seigo Usuki & Robert K. Yu

  2. Center for Molecular Chaperone/Radiobiology and Cancer Virology, Georgia Health Sciences University, Augusta, GA, 30912, USA

    Tetsu Kamitani & Yasuhiro Matsuo

Authors
  1. Seigo Usuki
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  2. Tetsu Kamitani
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  3. Yasuhiro Matsuo
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  4. Robert K. Yu
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Correspondence to Seigo Usuki.

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Usuki, S., Kamitani, T., Matsuo, Y. et al. Pathobiochemical Effect of Acylated Steryl-β-Glucoside on Aggregation and Cytotoxicity of α-Synuclein. Neurochem Res 37, 1261–1266 (2012). https://doi.org/10.1007/s11064-011-0662-4

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  • DOI: https://doi.org/10.1007/s11064-011-0662-4

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