Transient osmotic stress facilitates mutant huntingtin aggregation.
Human neuroblastoma SH-SY5Y cell lines stably expressing mutant truncated huntingtin with 82 (mutant) glutamine repeats (N63-82Q) were briefly exposed to hyperosmotic conditions which decrease cell volume and therefore transiently increased the concentration of N63-82Q, as well as activating specific stress-induced pathways. Transient hyperosmotic treatment significantly increased the number of cells with aggregates. When the N63-82Q cells were subsequently returned to iso-osmotic medium after the treatment, the number of cells with aggregates remained constant up to 12 h. However, between 12 and 24 h another significant increase in aggregate frequency was observed, with approximately 55% of the cells containing aggregates after 24 h. This may be due in part to the formation of microaggregates during hyperosmotic conditions that act as seeds for the aggregate formation. Further, treatment of cells with geldanamycin, which activates a heat shock response, significantly attenuated the hyperosmotic-induced increase in aggregate formation.
Chun
Wanjoo
W
Department of Psychiatry and Behavioral Neurobiology, 1720 7th Avenue South, SC1061, University of Alabama at Birmingham, Birmingham, AL 35294-0017, USA.
Lesort
Mathieu
M
Lee
Matthew
M
Johnson
Gail V W
GV
D016227:Benzoquinones; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018869:Heat-Shock Response / Q000187:drug effects / Q000502:physiology; D006801:Humans; D000071058:Huntingtin Protein; D006982:Hypertonic Solutions / Q000494:pharmacology; D047029:Lactams, Macrocyclic; D016296:Mutagenesis / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism*; D009447:Neuroblastoma; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism*; D009997:Osmotic Pressure; D011809:Quinones / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014882:Water-Electrolyte Balance / Q000502:physiology*
D016227:Benzoquinones; D004791:Enzyme Inhibitors; C086055:HTT protein, human; D000071058:Huntingtin Protein; D006982:Hypertonic Solutions; D047029:Lactams, Macrocyclic; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D011809:Quinones; C001277:geldanamycin