Abstract
Alpha-synuclein appears to play a role in mediating neurotoxicity in a number of neurodegenerative disorders, collectively referred to as synucleinopathies. Most of these disorders are associated with aging and a probable impairment of the proteasome-proteolytic pathway, although the relationship between aging, proteasome inhibition, and alpha-synuclein toxicity has not been fully elucidated. Recent studies suggest that yeast may provide a useful system for studying the biology and toxicity of alpha-synuclein in mitotic cells, recapitulating many features observed in the various synucleinopathy disorders. Additional studies indicate that the stationary phase model of aging in yeast provides a useful system for understanding the biochemistry and regulation of aging in post-mitotic cells. In the present study we examined the effect of wild type and mutant alpha-synuclein (A30P) on multiple aspects of proteasome homeostasis, protein synthesis, as well as the ability of cells to survive stationary phase aging. These data demonstrate that alpha-synuclein alters proteasome composition, impairs proteasome-mediated protein degradation, impairs protein synthesis, and impairs the ability of cells to withstand stationary phase aging. Interestingly, alpha-synuclein had little effect on intracellular proteasome content or protein ubiquitination, and did not increase the vulnerability of cells to a variety of stressors. Together, these data suggest that yeast may be useful for understanding the ability of alpha-synuclein to impair proteasome-mediated protein degradation, as well as for understanding the basis for age-related alpha-synuclein cytotoxicity.
Highlights
␣-Synuclein is a protein of as yet unknown function, which is believed to play a role in a wide array of neurodegenerative disorders including Dementia with Lewy bodies, Lewy body variant of Alzheimer disease, and Parkinson disease [1,2,3]
Wild Type and Mutant ␣-Synuclein Alter Proteasome-mediated Protein Degradation—To elucidate whether ␣-synuclein alters proteasome-mediated protein degradation, we quantified short-lived protein degradation, which is predominantly mediated by the proteasome [28, 31, 32, 37], in cells stably transformed with ␣-synuclein
These data are consistent with previous studies using reporters for proteasome-mediated protein degradation [17, 38, 39], which demonstrated ␣-synuclein-inhibited ubiquitindependent proteolysis, which was presumed to be primarily degraded by the proteasome
Summary
␣-Synuclein is a protein of as yet unknown function, which is believed to play a role in a wide array of neurodegenerative disorders including Dementia with Lewy bodies, Lewy body variant of Alzheimer disease, and Parkinson disease [1,2,3]. In the present study we conducted experimentation to understand the effects of wild type and mutant ␣-synuclein toward multiple aspects of cellular homeostasis including proteasome function, protein synthesis, and the ability to survive stationary phase aging These data demonstrate that ␣-synuclein has dramatic effects on proteasome-mediated protein degradation, protein synthesis, and impairs the ability of post-mitotic cells to survive stationary phase aging. Together, these data contribute to our understanding of ␣-synucleininduced cytotoxicity, and suggest that yeast may be useful for studying the effects of ␣-synuclein on steady state protein expression, as well as the aging-related cytotoxicity that is observed in a variety of synucleinopathies
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