Amyloid elimination by Hsp104 and substrate-optimized variants

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We are in dire need of innovations to combat several increasingly prevalent and inexorably lethal neurodegenerative disorders, including Alzheimer's and Parkinson's disease, which voraciously devour our social and economic resources. These disorders share a common pathogenic mechanism in which specific proteins misfold into a shared surprisingly generic conformation, termed amyloid. Amyloid fibers of diverse proteins adopt a similar `cross-β' structure, in which the strands of the β-sheets run perpendicular to the fiber axis. Further, highly cytotoxic oligomers possessing a distinct generic structure frequently accumulate prior to fibers. Although the specific protein that forms amyloid and precise localization of the deposits varies in each disease, these shared facets of amyloidogenesis bring hope that therapeutic strategies that target amyloid may have broad applications. The exceptional stability of amyloids, however, including: protease- and SDS-resistance, makes them extraordinarily difficult to clear. Indeed, they are widely perceived as intractable. Remarkably, we have found that a protein- remodeling factor from yeast, Hsp104, can rapidly disassemble amyloid fibers and oligomers comprised of the yeast prion proteins, Sup35 and Ure2. The unprecedented alacrity at which Hsp104 remodels these amyloid structures raises awareness that amyloid conformers are not intractable, and that a cellular factor capable of reversing amyloidogenesis has evolved. Curiously, although highly conserved in plants, bacteria and fungi, Hsp104 has been mysteriously lost from metazoan lineages. We hypothesize that application of Hsp104 to disease-associated amyloids may have broad therapeutic potential. Hence, we aim to: (1) annihilate amyloid fibers, oligomers and associated proteotoxicity of diverse human disease-associated proteins using Hsp104; (2) engineer or evolve substrate-optimized Hsp104 variants that attack select amyloidogenic proteins; and (3) generate Hsp104 or substrate-optimized variant therapies for animal models of amyloid-disorders. These studies will provide the foundations for new approaches to attack the devastating amyloid-disorders that plague humankind.