title: Dexamethasone induces heat shock response and slows down disease progression in mouse and fly models of Huntington's disease.
abstract: Huntington's disease (HD) is an inherited neurodegenerative disorder caused by abnormal expansion of glutamine repeats in the protein huntingtin. In HD brain, mutant huntingtin undergoes proteolytic processing, and its N-terminal fragment containing poly-glutamine repeats accumulate as insoluble aggregates leading to the defect in cellular protein quality control system and heat shock response (HSR). Here we demonstrate that the defective HSR in the brain is due to the down-regulation of heat shock factor 1 (HSF1) in both mice and fly models of HD. Interestingly, treatment of dexamethasone (a synthetic glucocorticoid) to HD mice or flies significantly increased the expression and transactivation of HSF1 and induction of HSR and these effects are mediated through the down-regulation of HSP90. Dexamethasone treatment also significantly decreased the aggregate load and transient recovery of HD-related behavioural phenotypes in both disease models. These results suggest that dexamethasone could be a potential therapeutic molecule for the treatment of HD and related poly-glutamine disorders.
authors.affiliation: Cellular and Molecular Neuroscience Laboratory, National Brain Research Centre, Manesar, Gurgaon 122 050, India.
authors.forename: Megha
authors.initials: M
authors.lastname: Maheshwari
authors.forename: Supriya
authors.initials: S
authors.lastname: Bhutani
authors.forename: Aniruddha
authors.initials: A
authors.lastname: Das
authors.forename: Rajarshi
authors.initials: R
authors.lastname: Mukherjee
authors.forename: Ankit
authors.initials: A
authors.lastname: Sharma
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kino
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Nukina
authors.forename: Nihar Ranjan
authors.initials: NR
authors.lastname: Jana
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D018450:Disease Progression; D004330:Drosophila; D004353:Drug Evaluation, Preclinical; D005260:Female; D005938:Glucocorticoids / Q000494:pharmacology* / Q000627:therapeutic use; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D000076249:Heat Shock Transcription Factors; D018869:Heat-Shock Response / Q000187:drug effects*; D006801:Humans; D006816:Huntington Disease / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011597:Psychomotor Performance / Q000187:drug effects; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation
chemical_list: D004268:DNA-Binding Proteins; D005938:Glucocorticoids; D018840:HSP70 Heat-Shock Proteins; D000076249:Heat Shock Transcription Factors; C490017:Hsf1 protein, mouse; D014157:Transcription Factors; D003907:Dexamethasone