The frequency of yeast [PSI+] prion formation is increased during chronological ageing

Abstract

Ageing involves a time-dependent decline in a variety of intracellular mechanisms and is associated with cellular senescence. This can be exacerbated by prion diseases which can occur in a sporadic manner, predominantly during the later stages of life. Prions are infectious, self-templating proteins responsible for several neurodegenerative diseases in mammals and several prion-forming proteins have been found in yeast. We show here that the frequency of formation of the yeast [PSI+] prion, which is the altered form of the Sup35 translation termination factor, is increased during chronological ageing. This increase is exacerbated in an atg1 mutant suggesting that autophagy normally acts to suppress age-related prion formation. We further show that cells which have switched to [PSI+] have improved viability during chronological ageing which requires active autophagy. [PSI+] stains show increased autophagic flux which correlates with increased viability and decreased levels of cellular protein aggregation. Taken together, our data indicate that the frequency of [PSI+] prion formation increases during yeast chronological ageing, and switching to the [PSI+] form can exert beneficial effects via the promotion of autophagic flux.

A prolonged chronological lifespan is an unexpected benefit of the [PSI+] prion in yeast

“…Importantly, curing had no effect on the survival rates of naïve [ psi - ] cells, indicating that neither the guanidine hydrochloride treatment nor other prions that may have been initially present in the cells are responsible for these observations ( Fig 1 , S1 Fig and S6 Fig ). In contrast with our findings, Speldewinde and Grant reported that cured cells had a shorter lifespan compared to [ PSI + ] cells [ 23 ]. It is important to note that these authors used five rounds of growth on guanidine hydrochloride-containing medium to cure cells [ 23 ], a harsh and selective treatment that could have unknown side-effects, as opposed to our gentler curing conditions sufficient to eliminate [ PSI + ] ( Fig 1C , S4 Fig and S5 Fig ), through two passages on guanidine hydrochloride-containing medium (see Materials and Methods section).…”

“…A prolonged chronological lifespan allowing cells to survive longer under such conditions would be a major selective advantage for yeasts in the wild, which could explain the extraordinary conservation of the prion-forming ability of Sup35p over one billion years of fungal evolution [ 22 ]. In agreement with our own findings, Speldewinde and Grant recently reported that [ PSI + ] improves chronological lifespan and proposed this could be due to an increased autophagic flux [ 23 ].…”

Growth phase‐dependent changes in the size and infectivity of SDS‐resistant Sup35p assemblies associated with the [PSI+] prion in yeast

“…To which extent the [PSI + ] variants affect the proteome is however still unclear (Baudin-Baillieu et al, 2014;Chan et al, 2017). [PSI + ] has been shown to facilitate the phenotypic manifestation of hidden genetic variation (True and Lindquist, 2000;True et al, 2004;Tyedmers et al, 2008;Halfmann et al, 2012), and we and others have recently showed that [PSI + ] cells have a longer chronological lifespan (Speldewinde and Grant, 2017;Wang et al, 2017).…”

Prion-dependent proteome remodeling in response to environmental stress is modulated by prion variant and genetic background

“…Viability assays were performed as previously described [50,51]. Briefly, colonies on SD agar medium (with or without ZnCl 2 ) were harvested in phosphate-buffered saline and incubated at 30°C for 30 minutes with 2 µM propidium iodide (Molecular Probes).…”