Dexamethasone induces heat shock response and slows down disease progression in mouse and fly models of Huntington's disease
| Autor: | Nihar Ranjan Jana, Megha Maheshwari, Yoshihiro Kino, Rajarshi Mukherjee, Ankit Sharma, Nobuyuki Nukina, Supriya Bhutani, Aniruddha Das |
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| Rok vydání: | 2014 |
| Předmět: |
Male
Transcriptional Activation medicine.medical_specialty Huntingtin Drug Evaluation Preclinical Mice Transgenic Biology Dexamethasone Cell Line Transactivation Huntington's disease Heat Shock Transcription Factors Internal medicine Genetics medicine Animals Humans HSP70 Heat-Shock Proteins Heat shock HSF1 Molecular Biology Glucocorticoids Genetics (clinical) Brain General Medicine medicine.disease Hsp90 Glutamine DNA-Binding Proteins Mice Inbred C57BL Disease Models Animal Endocrinology Huntington Disease biology.protein Disease Progression Drosophila Female Heat-Shock Response Psychomotor Performance medicine.drug Transcription Factors |
| Zdroj: | Human molecular genetics. 23(10) |
| ISSN: | 1460-2083 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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