Abstract
Protein quality control (PQC) is critical to maintain a functioning proteome. Misfolded or toxic proteins are either refolded or degraded by a system of temporal quality control and can also be sequestered into aggregates or inclusions by a system of spatial quality control. Breakdown of this concerted PQC network with age leads to an increased risk for the onset of disease, particularly neurological disease. Saccharomyces cerevisiae has been used extensively to elucidate PQC pathways and general evolutionary conservation of the PQC machinery has led to the development of several useful S. cerevisiae models of human neurological diseases. Key to both of these types of studies has been the development of several different model misfolding proteins, which are used to challenge and monitor the PQC machinery. In this review, we summarize and compare the model misfolding proteins that have been used to specifically study spatial PQC in S. cerevisiae, as well as the misfolding proteins that have been shown to be subject to spatial quality control in S. cerevisiae models of human neurological diseases.
Highlights
The presence of protein inclusions is a hallmark of many age-related neurological diseases (Kaytor and Warren, 1999; Koo et al, 1999; Paulson, 1999)
Though protein deposits are common to many neurological diseases, inclusions can be seen in aged neuronal cells of healthy animals (Fiori, 1987; Peters et al, 1991), reinforcing the idea that inclusions are a normal response of the protein quality control (PQC) machinery to misfolded proteins
The spatial quality control mechanisms handling several disease model proteins in yeast have not yet been extensively studied, it appears that amyloidogenic proteins in general are targeted to the insoluble protein deposit (IPOD) compartment, which has been shown using Htt mutant proteins (Kaganovich et al, 2008; Escusa-Toret et al, 2013)
Summary
The presence of protein inclusions is a hallmark of many age-related neurological diseases (Kaytor and Warren, 1999; Koo et al, 1999; Paulson, 1999). We review the major model proteins used in S. cerevisiae to study spatial PQC pathways and the role of spatial quality control in the molecular basis of human disease. Model misfolding proteins have helped to define the different quality control sites that have been identified in yeast (Kaganovich et al, 2008; Miller et al, 2015; Hill et al, 2017) (Figure 1).
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