The Toxic Effects of Pathogenic Ataxin-3 Variants in a Yeast Cellular Model

• DOI: 10.1371/journal.pone.0129727
• Publication Date: 2015-06-08T18:17:38Z
• Authors: Marcella Bonanomi; Cristina Visentin; Gaetano Invernizzi; Paolo Tortora; Maria Elena Regonesi
• Keywords: Chaperone (clinical); Proteostasis

Ataxin-3 (AT3) is a deubiquitinating enzyme that triggers an inherited neurodegenerative disorder, spinocerebellar ataxia type 3, when its polyglutamine (polyQ) stretch close to the C-terminus exceeds critical length. AT3 variants carrying expanded polyQ are prone associate with each other into amyloid toxic aggregates, which responsible for neuronal death ensuing neurodegeneration. We employed Saccharomyces cerevisiae as eukaryotic cellular model better clarify mechanism by disease. expressed three variants: one normal (Q26), (Q85) and truncated region lying from beginning of end protein (291Δ). found expression form caused reduction in viability, accumulation reactive oxygen species, imbalance antioxidant defense system loss cell membrane integrity, leading necrotic death. The variant also exerted qualitatively similar, albeit milder, effect on growth cytotoxicity, points involvement non-polyQ regions cytotoxicity. Guanidine hydrochloride, well-known inhibitor chaperone Hsp104, almost completely restored wild-type survival rate both 291Δ- Q85-expressing strains. This suggests aggregation toxicity mediated prion forms yeast proteins, this plays key role their propagation.