Self-perpetuating protein aggregates transmit prion diseases in mammals and heritable traits in yeast. De novo prion formation can be induced by transient overproduction of the corresponding prion-forming protein or its prion domain. Here, we demonstrate that the yeast prion protein Sup35 interacts with various proteins of the actin cortical cytoskeleton that are involved in endocytosis. Sup35-derived aggregates, generated in the process of prion induction, are associated with the components of the endocytic/vacuolar pathway. Mutational alterations of the cortical actin cytoskeleton decrease aggregation of overproduced Sup35 and de novo prion induction and increase prion-related toxicity in yeast. Deletion of the gene coding for the actin assembly protein Sla2 is lethal in cells containing the prion isoforms of both Sup35 and Rnq1 proteins simultaneously. Our data are consistent with a model in which cytoskeletal structures provide a scaffold for generation of large aggregates, resembling mammalian aggresomes. These aggregates promote prion formation. Moreover, it appears that the actin cytoskeleton also plays a certain role in counteracting the toxicity of the overproduced potentially aggregating proteins.Prions are protein isoforms that cause transmissible neurodegenerative diseases in mammals (for review, see reference 50) and control heritable traits in fungi (for review, see references 10 to 12). Most known prions are self-perpetuating amyloid-like ordered fibrous protein aggregates which propagate the prion state by immobilizing the soluble protein molecules of the same amino acid sequence. Saccharomyces cerevisiae prion [PSI ϩ ] is an aggregate of the translation termination factor Sup35. The prion domain of Sup35 is rich in glutamine (Q) and asparagine (N) residues, resembling poly-Q proteins, such as huntingtin, which is involved in Huntington's disease (for review, see reference 53). While recent data shed light on the major steps of propagation of the preexisting [PSI ϩ ] aggregates in yeast cells (for review, see references 12 and 47), the mechanism of initial prion formation from nonprion protein remains a mystery. It has been shown that de novo formation of the [PSI ϩ ] prion is induced by transient overproduction of the Sup35 protein or its prion domain (14,19). This process is usually efficient only in cells containing other QNrich protein aggregates, such as [PIN ϩ ], a prion form of Rnq1 (20, 22). Likewise, preexisting QN-rich prions promote aggregation and aggregation-related toxicity of heterologous poly-Q proteins expressed in yeast cells (33,38). Possibly, preexisting QN-rich aggregates either provide initial nucleation centers for aggregation of other QN-rich proteins or sequester unknown antiaggregation factors.Assembly of amyloid fibers resembles the assembly of cytoskeletal structures such as actin filaments. The QN-rich domain of Sup35 was shown to interact with the actin assembly protein Sla1 in the two-hybrid assay (4). Deletion of SLA1 decreases de novo induction of [PSI ϩ ] ...

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Fifteen percent of children with undiagnosed SCD presented initially with severe complications of the disease. The morbidity and mortality related to undiagnosed SCD underscores the need for a national neonatal screening program in Canada.