title: Designer protein disaggregases to counter neurodegenerative disease.
abstract: Protein misfolding and aggregation unify several devastating neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. There are no effective therapeutics for these disorders and none that target the reversal of the aberrant protein misfolding and aggregation that cause disease. Here, I showcase important advances to define, engineer, and apply protein disaggregases to mitigate deleterious protein misfolding and counter neurodegeneration. I focus on two exogenous protein disaggregases, Hsp104 from yeast and gene 3 protein from bacteriophages, as well as endogenous human protein disaggregases, including: (a) Hsp110, Hsp70, Hsp40, and small heat-shock proteins; (b) HtrA1; and (c) NMNAT2 and Hsp90. I suggest that protein-disaggregase modalities can be channeled to treat numerous fatal and presently incurable neurodegenerative diseases.
authors.affiliation: Department of Biochemistry and Biophysics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, United States of America. Electronic address: jshorter@mail.med.upenn.edu.
authors.forename: James
authors.initials: J
authors.lastname: Shorter
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics; D001435:Bacteriophages / Q000235:genetics; D050957:HSP110 Heat-Shock Proteins / Q000235:genetics*; D050956:HSP40 Heat-Shock Proteins / Q000235:genetics*; D050884:HSP72 Heat-Shock Proteins / Q000235:genetics*; D006360:Heat-Shock Proteins / Q000235:genetics*; D006801:Humans; D010300:Parkinson Disease / Q000235:genetics; D066263:Protein Aggregation, Pathological / Q000235:genetics; D017510:Protein Folding; D012441:Saccharomyces cerevisiae / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics*
chemical_list: D050957:HSP110 Heat-Shock Proteins; D050956:HSP40 Heat-Shock Proteins; D050884:HSP72 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D029701:Saccharomyces cerevisiae Proteins; C070972:HsP104 protein, S cerevisiae