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.
Highlights
Since the first detailed and widely recognized description of Huntington’s disease (HD) by George Huntington in 1872 (Hayden, 1981, 1983), there have been important advances in understanding this malady
Saccharomyces cerevisiae has a long-standing history in basic and applied research (Barnett, 2003), and the areas in which it can be used continue to expand in content and number
Many aspects of neurodegenerative processes lie beyond the capacity of yeast models, numerous important features of age-related and neurodegenerative diseases in general and HD in particular can reliably be modeled and studied in yeast
Summary
Since the first detailed and widely recognized description of Huntington’s disease (HD) by George Huntington in 1872 (Hayden, 1981, 1983), there have been important advances in understanding this malady. Poly(Q) toxicity of a human exon-1 fusion construct, as used in most models, is largely dependent on the flanking amino acid sequences Changes in these flanking regions affect both aggregation and cytotoxicity. Very similar results were obtained in vitro and in mammalian neuronal cell culture, showing that the importance of flanking regions for mHTT toxicity is not a yeast-specific artifact Both N- and C-terminal regions play an important role in mediating the aggregation dynamics, with the N-terminal amino acids favoring amyloid structures and the C-terminal poly(P) sequence slowing the process (Bhattacharyya et al, 2006; Crick et al, 2013). The capability to reproduce human glycosylation patterns will become interesting (Gasser et al, 2013), regarding its involvement in HTT toxicity
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