Alpha-synuclein alters proteasome function, protein synthesis, and stationary phase viability.
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.
Chen
Qinghua
Q
Sanders-Brown Center on Aging, The Department of Anatomy and Neurobiology, University of Kentucky, Lexington, Kentucky 40536, USA.
Thorpe
Jeffrey
J
Keller
Jeffrey N
JN
D002470:Cell Survival; D006801:Humans; D008938:Mitosis; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D018384:Oxidative Stress; D010957:Plasmids / Q000378:metabolism; D016133:Polymerase Chain Reaction; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D051843:Synucleins; D013997:Time Factors; D014357:Trypsin / Q000737:chemistry; D025801:Ubiquitin / Q000378:metabolism; D015003:Yeasts / Q000378:metabolism; D051844:alpha-Synuclein; D016875:tau Proteins / Q000737:chemistry
D009419:Nerve Tissue Proteins; C497604:SNCA protein, human; D051843:Synucleins; D025801:Ubiquitin; D051844:alpha-Synuclein; D016875:tau Proteins; D014357:Trypsin; D046988:Proteasome Endopeptidase Complex