Applying Hsp104 to protein-misfolding disorders.
Hsp104, a hexameric AAA+ ATPase found in yeast, transduces energy from cycles of ATP binding and hydrolysis to resolve disordered protein aggregates and cross-beta amyloid conformers. These disaggregation activities are often co-ordinated by the Hsp70 chaperone system and confer considerable selective advantages. First, renaturation of aggregated conformers by Hsp104 is critical for yeast survival after various environmental stresses. Second, amyloid remodeling by Hsp104 enables yeast to exploit multifarious prions as a reservoir of beneficial and heritable phenotypic variation. Curiously, although highly conserved in plants, fungi and bacteria, Hsp104 orthologues are absent from metazoa. Indeed, metazoan proteostasis seems devoid of a system that couples protein disaggregation to renaturation. Here, we review recent endeavors to enhance metazoan proteostasis by applying Hsp104 to the specific protein-misfolding events that underpin two deadly neurodegenerative amyloidoses. Hsp104 potently inhibits Abeta42 amyloidogenesis, which is connected with Alzheimer's disease, but appears unable to disaggregate preformed Abeta42 fibers. By contrast, Hsp104 inhibits and reverses the formation of alpha-synuclein oligomers and fibers, which are connected to Parkinson's disease. Importantly, Hsp104 antagonizes the degeneration of dopaminergic neurons induced by alpha-synuclein misfolding in the rat substantia nigra. These studies raise hopes for developing Hsp104 as a therapeutic agent.
Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, 805b Stellar-Chance Laboratories, 422 Curie Boulevard, Philadelphia, PA 19104, USA.
Shilpa
S
Vashist
Mimi
M
Cushman
James
J
Shorter
D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D006360:Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D018832:Molecular Chaperones / Q000378:metabolism; D011328:Prions / Q000378:metabolism; D011489:Protein Denaturation; D017510:Protein Folding; D051381:Rats; D012441:Saccharomyces cerevisiae / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism*; D051844:alpha-Synuclein / Q000378:metabolism
D016229:Amyloid beta-Peptides; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D011328:Prions; D029701:Saccharomyces cerevisiae Proteins; D051844:alpha-Synuclein