Conformational behavior and aggregation of ataxin-3 in SDS

• Published in: PloS one Vol. 8; no. 7; p. e69416
• Main Authors: Saunders, Helen M, Hughes, Victoria A, Cappai, Roberto, Bottomley, Stephen P
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 22.07.2013; Public Library of Science (PLoS)
• Subjects: Agglomeration; Aggregation behavior; Amyloid; Ataxia; Ataxin; Biochemistry; Biology; Cell membranes; Diseases; Fibrillogenesis; Hydrogen-Ion Concentration; Lipids; Machado-Joseph disease; Medicine; Membranes; Micelles; Molecular biology; Nerve Tissue Proteins - chemistry; Nerve Tissue Proteins - metabolism; Neurotoxicity; Pathogenesis; Peptides; Peptides - chemistry; Peptides - metabolism; Phospholipids; Phospholipids - metabolism; Physics; Polyglutamine diseases; Protein Multimerization - drug effects; Protein Structure, Quaternary - drug effects; Protein Structure, Secondary - drug effects; Proteins; Sodium; Sodium dodecyl sulfate; Sodium Dodecyl Sulfate - chemistry; Sodium Dodecyl Sulfate - pharmacology; Sodium lauryl sulfate; Solubility; Spectrum analysis; Studies; Surface active agents; Toxicity; Trinucleotide repeat diseases
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0069416

Spinocerebellar ataxia type 3 (SCA3) is one of nine polyglutamine (polyQ) diseases all characterized by the presence of intraneuronal inclusions that contain aggregated protein. Aggregation of ataxin-3, the causative protein of SCA3, has been well characterized in vitro, with both pathogenic and non-pathogenic length ataxin-3 undergoing fibrillogenesis. However, only ataxin-3 containing an expanded polyQ tract leads to SCA3. Therefore other cellular factors, not present in previous in vitro studies, may modulate aggregation during disease. The interactions between fibrillar species and cell membranes have been characterized in a number of amyloid diseases, including Huntington's Disease, and these interactions affect aggregation and toxicity. We have characterized the effects of the membrane mimetic sodium dodecyl sulfate (SDS) on ataxin-3 structure and aggregation, to show that both micellar and non-micellar SDS have differing effects on the two stages of ataxin-3 aggregation. We also demonstrate that fibrillar ataxin-3 binds phospholipids, in particular phosphorylated phosphotidylinositols. These results highlight the effect of intracellular factors on the ataxin-3 misfolding landscape and their implications in SCA3 and polyQ diseases in general are discussed.