Active HSF1 significantly suppresses polyglutamine aggregate formation in cellular and mouse models.
Polyglutamine diseases are inherited neurodegenerative diseases characterized by misfolding and aggregation of proteins possessing expanded polyglutamine repeats. As overexpression of some heat shock protein (Hsp) suppresses polyglutamine aggregates and cell death, it is assumed that combined overexpression of Hsps will suppress that more effectively. Here, we examined the impact of active forms of heat shock transcription factor 1 (HSF1), which induces a set of Hsps, on polyglutamine inclusion formation and disease progression. We found that active HSF1 suppressed polyglutamine inclusion formation more significantly than any combination of Hsps in culture cells, possibly by regulating expression of unknown genes, as well as major Hsps. We crossed R6/2 Huntington disease mice with transgenic mice expressing an active HSF1 (HSF1Tg). Analysis of the skeletal muscle revealed that the polyglutamine inclusion formation and its weight loss were improved in R6/2/HSF1Tg mice. Unexpectedly, the life span of R6/2/HSF1Tg mice was significantly improved, although active HSF1 is not expressed in the brain. These results indicated that active HSF1 has a strong inhibitory effect on polyglutamine aggregate formation in vivo and in vitro.
Fujimoto
Mitsuaki
M
Department of Biochemistry and Molecular Biology, Yamaguchi University School of Medicine, Ube 775-8505, Japan.
Takaki
Eiichi
E
Hayashi
Tetsuya
T
Kitaura
Yasushi
Y
Tanaka
Yasunori
Y
Inouye
Sachiye
S
Nakai
Akira
A
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D015153:Blotting, Western; D001842:Bone and Bones / Q000378:metabolism; D002460:Cell Line; D003433:Crosses, Genetic; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006367:HeLa Cells; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins / Q000378:metabolism; D006358:Hot Temperature; D006801:Humans; D006816:Huntington Disease / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D018482:Muscle, Skeletal / Q000378:metabolism; D009154:Mutation; D009474:Neurons / Q000378:metabolism; D010455:Peptides / Q000737:chemistry*; D010957:Plasmids / Q000378:metabolism; D017510:Protein Folding; D013997:Time Factors; D014157:Transcription Factors / Q000737:chemistry* / Q000378:metabolism
D004268:DNA-Binding Proteins; C000619706:HSF1 protein, human; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins; D010455:Peptides; D014157:Transcription Factors; D049452:Green Fluorescent Proteins; C097188:polyglutamine