Sodium dodecyl sulfate-insoluble oligomers are involved in polyglutamine degeneration.
In polyglutamine (polyQ) degeneration, disease protein that carries an expanded polyQ tract is neurotoxic. Expanded polyQ protein exists in different conformations that display distinct solubility properties. In this study, an inducible transgenic Drosophila model is established to define the pathogenic form of polyQ protein at an early stage of degeneration in vivo. We show that microscopic polyQ aggregates are neither pathogenic nor protective. Further, no toxic effect of sodium dodecyl sulfate (SDS) -soluble polyQ protein is observed in our model. By means of filtration, 2 forms of SDS-insoluble protein species are identified according to their size. Coexpression of an ATPase-defective form of the molecular chaperone Hsc70 (Hsc70-K71S) selectively reduces the abundance of the large SDS-insoluble polyQ species, but such modulation has no modifying effects on degeneration. Notably, we detect a distinct Hsc70-K71S-resistant, small, SDS-insoluble polyQ oligomeric species that is closely correlated with degeneration. Our data highlight the toxic role of SDS-insoluble oligomers in polyQ degeneration in vivo.
Wong
S L Alan
SL
Laboratory of Drosophila Research, The Chinese University of Hong Kong, Shatin NT, Hong Kong, China.
Chan
Wing Man
WM
Chan
H Y Edwin
HY
D000818:Animals; D004195:Disease Models, Animal; D004331:Drosophila melanogaster; D050883:HSC70 Heat-Shock Proteins / Q000096:biosynthesis; D051379:Mice; D019636:Neurodegenerative Diseases / Q000209:etiology*; D010455:Peptides / Q000737:chemistry / Q000378:metabolism*; D011487:Protein Conformation; D012967:Sodium Dodecyl Sulfate / Q000737:chemistry*; D012995:Solubility
D050883:HSC70 Heat-Shock Proteins; D010455:Peptides; C097188:polyglutamine; D012967:Sodium Dodecyl Sulfate