title: Multiple discrete soluble aggregates influence polyglutamine toxicity in a Huntington's disease model system.
abstract: Huntington's disease (HD) results from expansions of polyglutamine stretches (polyQ) in the huntingtin protein (Htt) that promote protein aggregation, neurodegeneration, and death. Since the diversity and sizes of the soluble Htt-polyQ aggregates that have been linked to cytotoxicity are unknown, we investigated soluble Htt-polyQ aggregates using analytical ultracentrifugation. Soon after induction in a yeast HD model system, non-toxic Htt-25Q and cytotoxic Htt-103Q both formed soluble aggregates 29S to 200S in size. Because current models indicate that Htt-25Q does not form soluble aggregates, reevaluation of previous studies may be necessary. Only Htt-103Q aggregation behavior changed, however, with time. At 6 hr mid-sized aggregates (33S to 84S) and large aggregates (greater than 100S) became present while at 24 hr primarily only mid-sized aggregates (20S to 80S) existed. Multiple factors that decreased cytotoxicity of Htt-103Q (changing the length of or sequences adjacent to the polyQ, altering ploidy or chaperone dosage, or deleting anti-aging factors) altered the Htt-103Q aggregation pattern in which the suite of mid-sized aggregates at 6 hr were most correlative with cytotoxicity. Hence, the amelioration of HD and other neurodegenerative diseases may require increased attention to and discrimination of the dynamic alterations in soluble aggregation processes.
authors.affiliation: Department of Molecular, Cellular, and Biomedical Sciences, Rudman Hall, University of New Hampshire, NH 03824, Durham, USA.
authors.forename: Wen
authors.initials: W
authors.lastname: Xi
authors.affiliation: Department of Molecular, Cellular, and Biomedical Sciences, Rudman Hall, University of New Hampshire, NH 03824, Durham, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Molecular, Cellular, and Biomedical Sciences, Rudman Hall, University of New Hampshire, NH 03824, Durham, USA.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Laue
authors.affiliation: Department of Molecular, Cellular, and Biomedical Sciences, Rudman Hall, University of New Hampshire, NH 03824, Durham, USA.
authors.forename: Clyde L
authors.initials: CL
authors.lastname: Denis
mesh_terms: D006801:Humans; D000071058:Huntingtin Protein / Q000235:genetics / Q000378:metabolism*; D006816:Huntington Disease / Q000503:physiopathology*; D008954:Models, Biological; D010455:Peptides / Q000235:genetics / Q000633:toxicity*; D066329:Protein Aggregates; D014461:Ultracentrifugation; D015003:Yeasts / Q000235:genetics / Q000378:metabolism
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; D010455:Peptides; D066329:Protein Aggregates; C097188:polyglutamine