Studying Huntington’s Disease in Yeast: From Mechanisms to Pharmacological Approaches

Abstract

Huntington’s disease (HD) is a neurodegenerative disorder that leads to progressive neuronal loss, provoking impaired motor control, cognitive decline, and dementia. So far, HD remains incurable, and available drugs are effective only for symptomatic management. HD is caused by a mutant form of the huntingtin protein, which harbors an elongated polyglutamine domain and is highly prone to aggregation. However, many aspects underlying the cytotoxicity of mutant huntingtin (mHTT) remain elusive, hindering the efficient development of applicable interventions to counteract HD. An important strategy to obtain molecular insights into human disorders in general is the use of eukaryotic model organisms, which are easy to genetically manipulate and display a high degree of conservation regarding disease-relevant cellular processes. The budding yeast Saccharomyces cerevisiae has a long-standing and successful history in modeling a plethora of human maladies and has recently emerged as an effective tool to study neurodegenerative disorders, including HD. Here, we summarize some of the most important contributions of yeast to HD research, specifically concerning the elucidation of mechanistic features of mHTT cytotoxicity and the potential of yeast as a platform to screen for pharmacological agents against HD.

Roles of Telomere Biology in Cell Senescence, Replicative and Chronological Ageing

“…The budding yeast post-mitotic cell ageing usually undergoes for 1–2 months of survival and has been widely used in ageing research [26,35,36,37,38,39,40,41,42]. It is believed that evolutionarily conserved key molecules in the polarization processes from yeast budding and mating to metazoan neuronal outgrowth and spinogenesis are homologous, potentially making the yeast chronological ageing process as a useful model for the non-dividing human cell ageing research [43,44,45,46,47,48,49].…”

Yeast Models for the Study of Amyloid-Associated Disorders and Development of Future Therapy

“…Since the establishment of the first HD model in yeast (Krobitsch and Lindquist, 2000), several additional yeast HD models have been described, employing the exogenous expression of poly-Q repeats at variable lengths under the control of different promoters (Hofer et al, 2018). In many cases, expression of the longer glutamine expansions, above a threshold not precisely defined in yeast, resulted in cytotoxicity (Solans et al, 2006; Kaiser et al, 2013; Papsdorf et al, 2015; Ruetenik et al, 2016).…”

“…This study demonstrated the formation of multiple types of aggregates, highly diverse in size and structure. This diversity indicates a complex set of molecular mechanisms underlying cell toxicity, currently hindering their full elucidation (Xi et al, 2016; Hofer et al, 2018). Interestingly, these analyses identified mid-sized aggregates to be associated with cell toxicity in yeast (Xi et al, 2016), in accordance with concurrent findings in mouse neuroblastoma cells (Kim et al, 2016), though in mammalian systems this issue is still under debate (Drombosky et al, 2018).…”

“…Several yeast models of amyloid-associated disorders have recently been comprehensively reviewed (Di Gregorio and Duennwald, 2018; Hofer et al, 2018; Lindström and Liu, 2018). Here, we overview the principal Saccharomyces cerevisiae models, focusing on the latest advancements they allowed to achieve.…”

Invertebrate and vertebrate models in aging research

“…It has helped in the elucidation of mechanistic features of mHTT cytotoxicity and has established the potential of yeast as a platform for screening for pharmacological agents against HD (ref. 28 ).…”