Abstract
Amyloids are self-perpetuating protein aggregates causing neurodegenerative diseases in mammals. Prions are transmissible protein isoforms (usually of amyloid nature). Prion features were recently reported for various proteins involved in amyloid and neural inclusion disorders. Heritable yeast prions share molecular properties (and in the case of polyglutamines, amino acid composition) with human disease-related amyloids. Fundamental protein quality control pathways, including chaperones, the ubiquitin proteasome system and autophagy are highly conserved between yeast and human cells. Crucial cellular proteins and conditions influencing amyloids and prions were uncovered in the yeast model. The treatments available for neurodegenerative amyloid-associated diseases are few and their efficiency is limited. Yeast models of amyloid-related neurodegenerative diseases have become powerful tools for high-throughput screening for chemical compounds and FDA-approved drugs that reduce aggregation and toxicity of amyloids. Although some environmental agents have been linked to certain amyloid diseases, the molecular basis of their action remains unclear. Environmental stresses trigger amyloid formation and loss, acting either via influencing intracellular concentrations of the amyloidogenic proteins or via heterologous inducers of prions. Studies of environmental and physiological regulation of yeast prions open new possibilities for pharmacological intervention and/or prophylactic procedures aiming on common cellular systems rather than the properties of specific amyloids.
Highlights
Yeast Prions and Protein Quality ControlRegardless of its relative simplicity, yeast harbors a significant number of cellular pathways and factors relevant to human neurodegeneration, including conserved chaperone and protein remodeling, the ubiquitin proteasome system, secretion, vesicular trafficking, and autophagy
Prions are self-perpetuating protein isoforms, usually of amyloid nature that are transmitted via extracellular infection in mammals
The abovementioned cytoskeleton-associated stress-inducible prionogenic protein, Lsb2, and its non-prionogenic paralog, Lsb1, partially protect [PSI+ ] from destabilization by mild heat shock, consistent with their general “pro-aggregation” effect [81,102]. Another prion eliminated by growth at a mildly elevated temperature is [SWI+ ] [27], the detailed mechanism of curing has not been deciphered in this case
Summary
Regardless of its relative simplicity, yeast harbors a significant number of cellular pathways and factors relevant to human neurodegeneration, including conserved chaperone and protein remodeling, the ubiquitin proteasome system, secretion, vesicular trafficking, and autophagy. Due to convenient genetic and phenotypic assays, yeast prions provide a useful model system for studying mechanisms of amyloid formation and propagation that are mostly applicable to mammalian and human diseases [12,13,14,15]. Cellular defense machineries such as chaperone proteins and the ubiquitin–proteasome system, aimed at protecting the cells from aggregation of stress-damaged proteins, recognize amyloid aggregates and stress-related proteins and serve as major modulators of prion formation and propagation in yeast [16,17,18,19,20,21]. Most components of the chaperone machinery are evolutionarily conserved, Hsp104 orthologs are not present in the cytosol of multicellular animals, including mammals. Further understanding of the mammalian chaperone machinery, associated with amyloids, is necessary for successful development in this direction
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