Loss of Metal Ions, Disulfide Reduction and Mutations Related to Familial ALS Promote Formation of Amyloid-Like Aggregates from Superoxide Dismutase

• DOI: 10.1371/journal.pone.0005004
• Publication Date: 2009-03-26T22:56:41Z
• Authors: Zeynep A. Oztug D...; Jeffrey A. Cohlberg; Phong Dinh; Shelby Padua; Krista Ehrenclou; Sean Downes; James K. Tan; Yoko Nakano; Christopher J. Bo...; Jessica L. Hoskins; Chuhee Kwon; Andrew Z. Mason; Jorge A. Rodriguez; Peter A. Doucette; Bryan F. Shaw; Joan Selverstone ...
• Keywords: Thioflavin; Amyloid (mycology); Congo red

Mutations in the gene encoding Cu-Zn superoxide dismutase (SOD1) are one of causes familial amyotrophic lateral sclerosis (FALS). Fibrillar inclusions containing SOD1 and that bind amyloid-specific dye thioflavin S have been found neurons transgenic mice expressing mutant SOD1. Therefore, formation amyloid fibrils from human was investigated. When agitated at acidic pH presence low concentrations guanidine or acetonitrile, metalated formed fibrillar material which bound both T Congo red had circular dichroism infrared spectra characteristic amyloid. While did not form amyloid-like aggregates neutral pH, either removing metals with its intramolecular disulfide bond intact reducing sufficient to promote these aggregates. without intermolecular bonds, depending on incubation conditions, a lacking free sulfhydryl groups (AS-SOD1) under conditions. ALS mutations enhanced ability disulfide-reduced aggregates, apo-AS-SOD1 7 only when an mutation also present. These results indicate some related by facilitating loss and/or making more susceptible reduction, thus allowing conversion resembling Furthermore, occurrence per se does depend forming multiple forms such can be produced