title: Pathobiochemical effect of acylated steryl-β-glucoside on aggregation and cytotoxicity of α-synuclein.
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.
authors: Institute of Molecular Medicine and Genetics, Georgia Health Sciences University, Augusta, GA 30912, USA. susuki@georgiahealth.edu
authors: Seigo
authors: S
authors: Usuki
authors: Tetsu
authors: T
authors: Kamitani
authors: Yasuhiro
authors: Y
authors: Matsuo
authors: Robert K
authors: RK
authors: Yu
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology; D000690:Amyotrophic Lateral Sclerosis / Q000139:chemically induced; D029784:Cycas / Q000737:chemistry; D003704:Dementia / Q000139:chemically induced; D005960:Glucosides / Q000633:toxicity*; D006801:Humans; D009498:Neurotoxins / Q000633:toxicity; D020734:Parkinsonian Disorders / Q000139:chemically induced; D057165:Proteostasis Deficiencies / Q000209:etiology; D012639:Seeds / Q000633:toxicity; D053835:Unilamellar Liposomes / Q000494:pharmacology; D051844:alpha-Synuclein / Q000187:drug effects / Q000378:metabolism* / Q000633:toxicity*
chemical_list: D005960:Glucosides; D009498:Neurotoxins; D053835:Unilamellar Liposomes; D051844:alpha-Synuclein; D000255:Adenosine Triphosphate