Prions are infectious protein isoforms that cause fatal and incurable neurodegenerative diseases in mammals and transmit heritable traits in yeast. Most prions form highly ordered fibrous polymers (amyloids), resembling the aggregates involved in other amyloidoses and neural inclusion diseases, such as Alzheimer, Parkinson, or Huntington diseases. Thus, a prion can be thought of as an amyloid that can recruit protein molecules of the same sequence, convert them into an amyloid state, and be transmitted to other cells. It is now becoming clear that in addition to their role in disease, some prions and other amyloids or amyloid-like aggregates perform important biological functions: storage of peptide hormones;attachment of microbial cells to each other or to substrates;control of epigenetic switches;adaptation to stressful environmental conditions;and long-term synaptic changes associated with memory. While many proteins form amyloids in vitro, little is known about the mechanisms of amyloid or prion formation in vivo. There are likely both basal and induced pathways that share some common features. An initial association of proteins in homomultimeric and/or heteromultimeric complexes may lead to formation of the prion "seed". The probability of such an event is increased when the amyloidogenic protein is accumulated at high concentrations in the cell and/or in a local compartment. Indeed, de novo formation of a yeast prion is promoted by overexpression of the prion protein and/or the presence of other aggregated QN-rich proteins. Processes known to affect protein levels and homeostasis, such as some physiological stresses, impairment of ubiquitin proteasome system (UPS) function, or defects in the unfolded protein response (UPR), also increase prion formation. Conversely, defects in the actin cytoskeleton diminish the rate of prion formation, suggesting that binding to cytoskeleton is important for some step(s) involved in prion nucleation. Thus, physiological stresses that cause the accumulation of prion proteins or heterologous prionogenic proteins, and that control their localization may have profound effects on the formation of prions. Lsb2 is a yeast protein whose overexpression stimulates the formation of a prion (designated [PSI+]) in the presence of overexpression of the yeast translational termination factor Sup35. Consistent with its role in prionogenesis, Lsb2 is induced by stress, ubiquitinated at K80, degraded in a proteasome-dependent fashion, and localized to actin patches. The overall goal of this research is to uncover the molecular mechanisms by which heterologous protein homeostasis participates in prion formation in eukaryotic cells. We will define the role of Lsb2 in the stress-induced formation of the [PSI+] prion. We will ask if a specific cellular localization of Lsb2 is required for prion-inducing ability, what role UPS and covalent modifications of Lsb2 play in triggering the formation of prions, and if physiological and stress- related variations in Lsb2 levels are involved in prion induction.
Prions are infectious protein isoforms that cause fatal and incurable neurodegenerative diseases in mammals. Most prions form highly ordered fibrous polymers (amyloids), resembling the aggregates involved in other amyloidoses and neural inclusion diseases, such as Alzheimer, Parkinson, or Huntington diseases. Little is known about how prions are formed in vivo. By elucidating the general mechanisms regulating prion formation in eukaryotic cells, our studies will help define an approach to interventions that may prevent formation of prions and other amyloid deposits.
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