4.4 Article

A Yeast Chronological Lifespan Assay to Assess Activity of Proteasome Stimulators

Journal

CHEMBIOCHEM
Volume 22, Issue 15, Pages 2553-2560

Publisher

WILEY-V C H VERLAG GMBH
DOI: 10.1002/cbic.202100117

Keywords

Bioconjugation; CLS; photodynamic; porphyrins; proteasome; stimulator; yeast

Funding

  1. Purdue University School of Pharmacy
  2. Purdue University Center for Cancer Research NIH [P30 CA023168]
  3. NIH-NIGMS [R21GM131206]

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Long-lived rodents have shown elevated proteasome activity, while proteasome dysfunction is linked to shorter lifespan in transgenic mice. The impact of proteasome stimulators on yeast with impaired proteasome expression and wild-type yeast can be evaluated using developed techniques. Small molecule stimulators may have potential to increase chronological lifespan in eukaryotic model organisms.
Aging is characterized by changes in several cellular processes, including dysregulation of proteostasis. Current research has shown long-lived rodents display elevated proteasome activity throughout life and proteasome dysfunction is linked to shorter lifespans in a transgenic mouse model. The ubiquitin proteasome system (UPS) is one of the main pathways leading to cellular protein clearance and quality maintenance. Reduction in proteasome activity is associated with aging and its related pathologies. Small molecule stimulators of the proteasome have been proposed to help alleviate cellular stress related to unwanted protein accumulation. Here we have described the development of techniques to monitor the impact of proteasome stimulation in wild-type yeast and a strain that has impaired proteasome expression. We validated our chronological lifespan assay using both types of yeast with a variety of small molecule stimulators at different concentrations. By modifying the media conditions for the yeast, molecules can be evaluated for their potential to increase chronological lifespan in five days. Additionally, our assay conditions can be used to monitor the activity of proteasome stimulators in modulating the degradation of a YFP-alpha-synuclein fusion protein produced by yeast. We anticipate these methods to be valuable for those wishing to study the impact of increasing proteasome-mediated degradation of proteins in a eukaryotic model organism.

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