The Toxic Effects of Pathogenic Ataxin-3 Variants in a Yeast Cellular Model
0301 basic medicine
Saccharomyces cerevisiae Proteins
Science
Apoptosis
Saccharomyces cerevisiae
Models, Biological
Antioxidants
Protein Aggregates
03 medical and health sciences
Humans
yeast; neurodegeneration; ataxin 3; polyQ toxicity; amyloid aggregates
Ataxin-3
Guanidine
Heat-Shock Proteins
0303 health sciences
Q
R
Sodium Dodecyl Sulfate
16. Peace & justice
3. Good health
Oxidative Stress
Solubility
Medicine
Mutant Proteins
Research Article
Molecular Chaperones
Propidium
DOI:
10.1371/journal.pone.0129727
Publication Date:
2015-06-08T18:17:38Z
AUTHORS (5)
ABSTRACT
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 a critical length. AT3 variants carrying the expanded polyQ are prone to associate with each other into amyloid toxic aggregates, which are responsible for neuronal death with ensuing neurodegeneration. We employed Saccharomyces cerevisiae as a eukaryotic cellular model to better clarify the mechanism by which AT3 triggers the disease. We expressed three variants: one normal (Q26), one expanded (Q85) and one truncated for a region lying from the beginning of its polyQ stretch to the end of the protein (291Δ). We found that the expression of the expanded form caused reduction in viability, accumulation of reactive oxygen species, imbalance of the antioxidant defense system and loss in cell membrane integrity, leading to necrotic death. The truncated variant also exerted a qualitatively similar, albeit milder, effect on cell growth and cytotoxicity, which points to the involvement of also non-polyQ regions in cytotoxicity. Guanidine hydrochloride, a well-known inhibitor of the chaperone Hsp104, almost completely restored wild-type survival rate of both 291Δ- and Q85-expressing strains. This suggests that AT3 aggregation and toxicity is mediated by prion forms of yeast proteins, as this chaperone plays a key role in their propagation.
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