A toxic monomeric conformer of the polyglutamine protein.
Polyglutamine (polyQ) diseases are classified as conformational neurodegenerative diseases, like Alzheimer and Parkinson diseases, and they are caused by proteins with an abnormally expanded polyQ stretch. However, conformational changes of the expanded polyQ protein and the toxic conformers formed during aggregation have remained poorly understood despite their important role in pathogenesis. Here we show that a beta-sheet conformational transition of the expanded polyQ protein monomer precedes its assembly into beta-sheet-rich amyloid-like fibrils. Microinjection of the various polyQ protein conformers into cultured cells revealed that the soluble beta-sheet monomer causes cytotoxicity. The polyQ-binding peptide QBP1 prevents the toxic beta-sheet conformational transition of the expanded polyQ protein monomer. We conclude that the toxic conformational transition, and not simply the aggregation process itself, is a therapeutic target for polyQ diseases and possibly for conformational diseases in general.
Nagai
Yoshitaka
Y
Division of Clinical Genetics, Department of Medical Genetics, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan. nagai@clgene.med.osaka-u.ac.jp
Inui
Takashi
T
Popiel
H Akiko
HA
Fujikake
Nobuhiro
N
Hasegawa
Kazuhiro
K
Urade
Yoshihiro
Y
Goto
Yuji
Y
Naiki
Hironobu
H
Toda
Tatsushi
T
D000682:Amyloid / Q000187:drug effects; D000818:Animals; D019556:COS Cells; D016923:Cell Death / Q000187:drug effects; D002522:Chlorocebus aethiops; D018625:Microscopy, Atomic Force; D046529:Microscopy, Electron, Transmission; D008954:Models, Biological; D009842:Oligopeptides / Q000378:metabolism; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity*; D020836:Protein Structure, Quaternary / Q000187:drug effects; D017433:Protein Structure, Secondary / Q000187:drug effects; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012995:Solubility / Q000187:drug effects
D000682:Amyloid; D009842:Oligopeptides; D010455:Peptides; D011993:Recombinant Fusion Proteins; C407346:polyglutamine-binding protein 1; C097188:polyglutamine