Abstract
Over the last few decades, the budding yeast Saccharomyces cerevisiae has been extensively used as a valuable organism to explore mechanisms of aging and human age-associated neurodegenerative disorders. Yeast models can be used to study loss of function of disease-related conserved genes and to investigate gain of function activities, frequently proteotoxicity, exerted by non-conserved human mutant proteins responsible for neurodegeneration. Most published models of proteotoxicity have used rapidly dividing cells and suffer from a high level of protein expression resulting in acute growth arrest or cell death. This contrasts with the slow development of neurodegenerative proteotoxicity during aging and the characteristic post-mitotic state of the affected cell type, the neuron. Here, we will review the efforts to create and characterize yeast models of neurodegeneration using the chronological life span model of aging, and the specific information they can provide regarding the chronology of physiological events leading to neurotoxic proteotoxicity-induced cell death and the identification of new pathways involved.
Highlights
Over the last few decades, the budding yeast Saccharomyces cerevisiae has been extensively used as a valuable organism to explore mechanisms of aging and human age-associated neurodegenerative disorders
Some disease genes are conserved along evolution, some of those responsible for age-associated neurodegenerative disorders are restricted to vertebrates
While many features of the disease cannot be modeled in yeast, yeast models have proven to provide a robust paradigm for the elucidation of pathways leading to cell death upon deletion or overexpression of conserved genes, or upon heterologous expression of human disease genes
Summary
The unicellular yeast Saccharomyces cerevisiae, known as baker’s yeast or brewer’s yeast, has been extensively used in the areas of biotechnology and biomedicine. Over the last two decades, yeast has been used to model the human aging process and complex neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), and Huntington’s disease (HD) (reviewed in Miller-Fleming et al, 2008). Mutant forms of the proteins huntingtin (htt) and α-synuclein, responsible for HD and some familiar forms of PD, respectively, undergo misfolding and damage several cellular structures leading to cell death Yeast models of these disorders are constructed by expressing the human disease gene in yeast providing paradigms where the toxic effect of the misfolded protein on the cellular physiology and metabolism can be conveniently studied (Outeiro and Lindquist, 2003; Willingham et al, 2003; Ocampo et al, 2010). THE YEAST CHRONOLOGICAL LIFE SPAN ASSAY: A BETTER SYSTEM TO MODEL NEURODEGENERATION?
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